MX2011006515A - Isoquinoline derivative. - Google Patents

Isoquinoline derivative.

Info

Publication number
MX2011006515A
MX2011006515A MX2011006515A MX2011006515A MX2011006515A MX 2011006515 A MX2011006515 A MX 2011006515A MX 2011006515 A MX2011006515 A MX 2011006515A MX 2011006515 A MX2011006515 A MX 2011006515A MX 2011006515 A MX2011006515 A MX 2011006515A
Authority
MX
Mexico
Prior art keywords
group
formula
compound
phenyl
solution
Prior art date
Application number
MX2011006515A
Other languages
Spanish (es)
Inventor
Takayama Tetsuo
Asanuma Hajime
Wakasugi Daisuke
Nishikawa Rie
Sekiguchi Yoshinori
Kawamura Madoka
Ono Naoya
Yabuuchi Tetsuya
Oi Takahiro
Oka Yusuke
Kuroda Shoichi
Uneuchi Fumito
Koami Takeshi
Original Assignee
Taisho Pharma Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Taisho Pharma Co Ltd filed Critical Taisho Pharma Co Ltd
Publication of MX2011006515A publication Critical patent/MX2011006515A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals
    • C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Dermatology (AREA)
  • Immunology (AREA)
  • Otolaryngology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

A compound represented by formula (I) or a pharmaceutically acceptable salt thereof has an effect of inhibiting CRTH2 and, therefore, is useful as a preventive or a remedy for allergic diseases such as asthma, atopic dermatitis and allergic rhinitis.

Description

DERIVATIVE OF ISOQUINOLI A TECHNICAL FIELD The present invention is concerned with a compound having an inhibitory effect on CRTH2 (receptor-homologous chemoattractant molecule expressed on Th2 cells), and pharmaceutical preparations containing the compound as an active ingredient.
BACKGROUND OF THE INVENTION CRTH2 is a 7th transmembrane domain molecule coupled to the G protein cloned by Nagata et al. in 1999 as a molecule expressed selectively on Th2 cells (see document that is not patent 1).
It has been reported that the Th2 cell is a form of activated T cells and induces the production of IgE from B cells via the production of cytokines such as IL-4, IL-5, and IL-13 (see document that is not Patent 2). In addition, it has been reported that cytokines induce the activation of eosinophil and basophil (see documents that are not patent 3 and 4). From the previous reports, it has been believed that Th2 cells are strongly involved in the formation of pathological conditions of allergic diseases such as asthma, allergic rhinitis, and atopic dermatitis directly or indirectly via other cells or factors (see document that is not of patent 5).
Because CRTH2 is cloned as a molecule selectively expressed on the Th2 cell as mentioned above, and also has a relatively high homology to a chemokine receptor (see non-patent document 6), it has been assumed that CRTH2 is involved in immune responses or immune-related disorders. After this, it has been revealed that CRTH2 is expressed in eosinophil and basophil in addition to the Th2 cell and that the ligand is PGD2 and the action thereof induces a cell migration reaction and the like (see document which is not patent 7) . In particular, it has been suggested that CRTH2 is involved in allergic diseases.
In addition to such in vitro tests, in exacerbation of symptoms in an asthma model by a CRTH2-specific ligand and in a dermatitis model (see non-patent document 8), the suppression of symptoms in dermatitis in a defective CRTH2 mouse (see document that is not patent 9), increase in the expression of CRTH2 in human patients with allergic rhinitis (document that is not patent 10) and the like, has been reported the possibility that CRTH2 is involved in allergic diseases such as asthma, atopic dermatitis and allergic rhinitis. From such information, the possibility of creating therapeutic agents for the diseases mentioned above, which have a CRTH2 inhibition mechanism has been suggested.
Conventionally, as inhibitors of CRTH2, indolyl acetic acid derivatives (see patent document 1), phenoxy acetic acid derivatives (see patent document 2), pyrimidinyl acetic acid derivative (see patent document 3) and the like have been reported. However, a compound having the structure of the present invention has not been disclosed. In addition, although a compound of which the structure is similar to that of the compound of the present invention has been reported, there is neither description nor suggestion that such compounds have an inhibitory effect of CRTH2 (see patent document 4).
Previous Art Document Patent Documents Patent Document 1: WO2005 / 019171 Patent Document 2: WO2005 / 115382 Patent document 3: WO2004 / 096777 Patent document 4: WO2004 / 101528 Non-Patent Documents Document that is not patent 1: Nagata. et al. J. Immunol. 162. 1278. 1999 Document that is not patent 2: Del Prete. et al. Allergy. 47. 450; 1992 Document that is not patent 3: Pope, et al. J. Allergy. Clin. Immunol. 108. 594. 2001 Document that is not patent 4: Min. Et al. Curr.
Opin. Hematol. 15. 59. 2008 Document that is not patent 5: Broide. et al. J. Allergy. Clin. Immunol. 108 (2 suppl.). S65. 2001 Document that is not patent 6: Abe. et al. Gene. 227. 71. 1999 Document that is not patent 7: Hirai. et al. J. Exp. Med. 193. 225. 2001 Document that is not patent 8: Shiraishi. et al. J. Pharmacol. Exp. Ther. 312. 954. 2005 Document that is not patent 9: Satoh. et al. J.
Immunol. 177. 2621. 2006 Document that is not patent 10: Kano. et al. Am. J. Rhinol. 20. 342. 2006.
BRIEF DESCRIPTION OF THE INVENTION Problem to be Solved by the Invention An object of the present invention is to provide a compound having an inhibitory effect on CRTH2 and which is useful as pharmaceutical preparations.
Means to Solve the Problem The present inventors have carried out investigations to obtain the aforementioned objects and the result was the finding that new isoquinoline derivatives obtain the mentioned object above and have come to the present invention.
That is, the present invention is: (1) a compound represented by the Formula [Ka 1] or a pharmaceutically acceptable salt thereof.
In the formula, R1 represents a Ci_6 alkyl group, a C2-6 alkenyl group, a C3_6 cycloalkyl group, a C3_6 cycloalkenyl group, an adamantyl group, an indanyl group, a tetrahydronaphthyl group, a tetrahydroindolyl group, a tetrahydropyranyl group, a group morpholinyl, a phenyl group, a naphthyl group, or an aromatic heterocyclic group, wherein the phenyl group, the naphthyl group and the aromatic heterocyclic group may be substituted with 1 to 5 substituent (s) selected from the group consisting of a group Ci_6 alkyl, a C2-6 alkenyl group, a C3-6 cycloalkyl group, a halogen atom, a Ci_6 alkoxy group, a hydroxy group, a Ci-6 alkylthio group, a Ci_6 haloalkyl group, a Ci-6 haloalkoxy group, a Ci_6 haloalkylthio group, a cyano group, a nitro group, a guanidino group, a Ci-6 alkylsulfonyl group, a carboxy group, a C 2-7 alkoxycarbonyl group, a C 2-7 group alkanoyloxy, a phenyl group, a benzoyl group, a phenoxy group, a pyrrolyl group ,. a thienyl group, an imidazolyl group, a thiadiazolyl group, a morpholino group, the formula: -NR5R6, the formula: S02NR7R8, the formula: -NR9S02R10, the formula: -CONRnR12, and the formula: -NR13COR14, wherein R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14 each independently represent a hydrogen atom or a Ci-6 alkyl group; X represents an oxygen atom, a sulfur atom, the formula: -CH2-, the formula: -C0-, or the formula: -NR2-, wherein R2 represents a hydrogen atom or a Ci_6 alkyl group; Y represents a single bond, the formula: -NR3CO-W-, the formula: -NR3CO-W-0-, the formula: NR3C02-W-, the formula: -NR3-W-, the formula: - R3S02-W -, the formula: - R3CONR4-W-, the formula: - R3CO-W- R S02-, the formula: -S02NR3-W-, the formula: -CH2-W-, the formula: -CONR3-W-, the formula: -CONR3-W-0-, the formula: -CH2-0-W-, the formula: -CH2NR3-W-, the formula: -CONR3-W-NRCO-, the formula: -OW-, or the formula: -OWO-, wherein R3 and R4 each independently represent a hydrogen atom or a Ci-6 alkyl group, W is a single bond, a Ci-6 alkylene group, a C2.6 alkylene group including a carbon atom which is also a member of a C3-6 cycloalkyl ring, a C2_6 alkenylene group, or a C3.6 cycloalkylene group (provided that, when Y is the formula: - CONR3-W-NR4CO- or the formula: -0-W-O-, W is not a single bond); Z is a benzene ring, a pyrimidine ring or a pyrazine ring; Ra is a carboxy group, a carbamoyl group, a tetrazolyl group or the formula: -CONHOH; Rb and R each independently represent a hydrogen atom, a halogen atom, or a Ci_6 alkyl group; Y Rd, Re, Rf and Rg each independently represent a hydrogen atom, a halogen atom, a Ci-6 alkyl group or a Ci-6 alkoxy group (provided that the compound is not acidic. - (butan-2-yloxy) benzyl] -6, 7-dimethoxyisoquinolin-4-yl} acetic acid (1- {[[3- (butan-2-yl) phenyl] carbonyl} -6,7-dimethoxyisoquinolin-4-yl) acetic acid (l- { [3- (butan -2-yloxy) phenyl] carbonyl.} - 6,7-dimethoxyisoquinolin-4-yl) acetic acid, 2- (6,7-dimethoxy-1 - {- [3- (propan-2-yloxy) phenyl] carbonyl, isoquinolin-4-yl) acetamide, (6,7-dimethoxy-1 - {- [3- (propaned-2-yloxy) phenyl] carbonyl} isoquinolin-4-yl) acetic acid, -. { 6,7-dimethoxy-l- [(3-methoxyphenyl) carbonyl] isoquinolin-4-yl} acetamide, or acid. { 6,7-dimethoxy-l- [(3-methoxy-phenyl) carbonyl] isoquinolin-4-yl} acetic). (2) The compound or a pharmaceutically acceptable salt thereof as set forth in (1), wherein Rd, Re, Rf and R9 each independently represent a hydrogen atom, a halogen atom, a Ci_6 alkyl group, or a Ci-6 alkoxy group (except the compound or a pharmaceutically acceptable salt thereof in which both of Rd and R9 are hydrogen atoms and both Re and Rf are Ci_6 alkoxy groups). (3) The compound or a pharmaceutically acceptable salt thereof as stated in (1) or (2), wherein: R1 is a Ci-6 alkyl group, a C2-6 alkenyl group, a C3_6 cycloalkyl group, a C3-6 cycloalkenyl group, an adamantyl group, an indanyl group, a tetrahydronaphthyl group, a tetrahydroindolyl group, a tetrahydropyranyl group, a group morpholinyl, a phenyl group, a naphthyl group or an aromatic heterocyclic group, wherein the phenyl group, the naphthyl group or the aromatic heterocyclic group may be substituted with 1 to 5 substituent (s) selected from the group consisting of a Ci- 6 alkyl, a C2-6 alkenyl group, a C3-6 cycloalkyl group, a halogen atom, a Ci-6 alkoxy group, a hydroxy group, a Ci_6 haloalkyl group, a Ci-6 haloalkoxy group, a cyano group, a nitro group, a Ci-6 alkylsulfonyl group, a carboxy group, a phenyl group, a benzoyl group, a phenoxy group, the formula: -NR5R6, and the formula: -S02NR7R8; X is an oxygen atom, the formula: -CH2-, or the formula: -C0-; Z is a benzene ring; Ra is a carboxy group, a carbamoyl group, a tetrazolyl group or the formula: -CONHOH; Rb and Rc each independently represent a hydrogen atom, or a Ci-6 alkyl group; Y Rd, Re, Rf and Rs each independently represent a hydrogen atom, a halogen atom or a Ci-6 alkoxy group.
The compound or a pharmaceutically acceptable salt thereof as stated in (1), wherein: R1 is a Ci_6 alkyl group, a C3-6 cycloalkyl group, a phenyl group, a naphthyl group, or an aromatic heterocyclic group, wherein the phenyl group,. the naphthyl group, "and the aromatic heterocyclic group can be substituted with 1 to 3 substituent (s) selected from the group consisting of a C 1-6 alkyl group, a halogen atom, a C 1-6 alkoxy group, a hydroxy group, a C 1-6 alkylthio group, a C 1-6 haloalkyl group, a C 1-6 haloalkoxy group, a C 1-6 haloalkylthio group, a cyano group, a nitro group, a guanidino group, a C 1-6 alkylsulfonyl group, a carboxy group, a C 2 group -7-alkoxycarbonyl, a C2-7 alkanoyloxy group, a phenyl group, a phenoxy group, a pyrrolyl group, a thienyl group, an imidazolyl group, a thiadiazolyl group, a morpholino group, the formula: -NR5R6, the formula: -S02NR7R8 , the formula: -NR9S02R10, the formula: -CO R ^ R12, and the formula: -NR13COR14; And it is a single 'link, the formula: - R3C0-W-, the formula: -NR3C0-W-0-, the formula: NR3C02-W-, the formula: -NR3-W- , the formula: -NR3S02-W-, the formula: -NR3CONR -W-, the formula: -CONR3-W-, the formula: -O-W-, the formula: -CH20-, or the formula: -CH2NR3-; W is a single bond, a Ci_6 alkylene group, a C2_6 group group, or a C3-6 cycloalkylene group; Ra is a carboxy group; Rb and Rc are each a hydrogen atom, and Rd, Re, Rf and Rg are each a hydrogen atom.
The compound or a pharmaceutically acceptable salt thereof as stated in (1), wherein: R1 is a C1-6 alkyl group, a C3-6 cycloalkyl group, a phenyl group, a naphthyl group, or an aromatic heterocyclic group, wherein the phenyl group, the naphthyl group, and the aromatic heterocyclic group may be substituted with to 3 substituent (s) selected from the group consisting of a Ci-6 alkyl group, a halogen atom, a C 1-6 alkoxy group, a C 1-6 haloalkyl group, a C 1-6 haloalkoxy group, a cyano group, a nitro group, a phenyl group, a phenoxy group, and the formula: -NR5R6; X is the formula: -CH2-, or the formula: -CO-; Y is the formula: -NR3CO-W-, the formula: -NR3CO-W-0-, the formula: - R3C02-W-, the formula: -NR3-W-, the formula: - R3S02-W-, the formula: -NR3CONR4-W-, or the formula: -OW-; W is a single bond, a Ci-6 alkylene group, a C2-6 alkenylene group, or a C3-6 cycloalkylene group; Z is a benzene ring; Ra is a carboxy group; Rb and Rc are each a hydrogen atom, and Rd, Re, R £ and R9 are each one hydrogen atom. (6) The compound or a pharmaceutically acceptable salt thereof as stated in (1), which is represented by the formula (II): [Ka 2] In the formula, R1 'is a C3-6 cycloalkyl group, a C3-6 cycloalkenyl group, an adamantyl group, an indanyl group, a tetrahydronaphthyl group, a tetrahydroindolyl group, a phenyl group, a naphthyl group, or an aromatic heterocyclic group, wherein the Phenyl group, the naphthyl group, and the aromatic heterocyclic group can be substituted with 1 to 5 substituent (s) selected from the group consisting of a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 3-6 cycloalkyl group, a halogen atom, a C 1-6 alkoxy group, a hydroxy group, a C 1-6 haloalkyl group, a C 1-6 haloalkoxy group, a cyano group, a nitro group, a C 1-6 alkylsulfonyl group, a phenyl group, a benzoyl group , a phenoxy group, the formula: -NR5R6, and the formula: -S02NR7R8, wherein R5, R6, R7, and R8 each independently represent a hydrogen atom or a Ci_6 alkyl group; X 'is the formula: -CH2-, or the formula: -C0-; Y W is a single bond, a Ci_6 alkylene group, a C2-6 alkenylene group, or a C3-6 cycloalkylene group. (7) The compound or a pharmaceutically acceptable salt thereof as stated in (6), wherein: R1 'is a C3-6 cycloalkyl group, a tetrahydronaphthyl group, a tetrahydroindolyl group, a phenyl group, a naphthyl group, an indolyl group, a benzofuranyl group, a benzothienyl group, a quinolyl group, or an isoquinolyl group, wherein the Phenyl group, the naphthyl group, the indolyl group, the benzofuranyl group, the benzothienyl group, the quinolyl group, or the isoquinolyl group can be substituted with 1 to 3 substituent (s) selected from the group consisting of a Ci_6 alkyl group, a halogen atom, a C 1-6 alkoxy group, a C 1-6 haloalkyl group, a C 1-6 haloalkoxy group, a cyano group, a nitro group, a phenyl group, a phenoxy group and the formula: -NR 5 R 6. (8) The compound or a pharmaceutically acceptable salt thereof as set forth in (6), wherein R1 'is a phenyl group, which may be substituted with 1 to 3 substituent (s) selected from the group consisting of a C1 group -6 alkyl, a halogen atom, a C1-6 alkoxy group, a C1-6 haloalkyl group, a Ci-6 haloalkoxy group, a group cyano, a nitro group, a phenyl group, a phenoxy group, and the formula: -NR5R6; Y W is a single link. (9) The compound or a pharmaceutically acceptable salt thereof as claimed in any of (6) to (8), wherein X 'is the formula: -CH2-. (10) The compound or a pharmaceutically acceptable salt thereof as claimed in (8), wherein X 'is the formula: -CO-. (11) The compound or a pharmaceutically acceptable salt thereof as set forth in (1) which is represented by the formula (III): [Ka 3] In the formula, R1"is a C3 -6 cycloalkyl group, a C3.6 cycloalkenyl group, an adamantyl group, a tetrahydronaphthyl group, a tetrahydroindolyl group, a phenyl group, a naphthyl group, or an aromatic heterocyclic group, wherein the phenyl group, the naphthyl group, and the aromatic heterocyclic group may be substituted with 1 to 5 substituent (s) selected from the group consisting of Ci-6 alkyl group, a C3-6 cycloalkyl group, a halogen atom, a Ci-6 alkoxy group, a hydroxy group, a Ci-6 haloalkyl group, a Ci_6 haloalkoxy group, a cyano group, a nitro group, a phenyl group, a phenoxy group, and the formula: -NR5R6; R5 and R6 each independently represent a hydrogen atom or a Ci_6 alkyl group; X "is the formula: -CH2-, or the formula: -C0-; and W" is a single bond, a C2-6 alkylene group that includes a carbon atom that is also a member of a C3-6 ring cycloalkyl, or a C 1-6 alkylene group. (12) The compound or pharmaceutically acceptable salt thereof as stated in (11), R1"is a C3-6 cycloalkyl group, an adamantyl group, a tetrahydronaphthyl group, a phenyl group, a naphthyl group, an indolyl group, a benzothiazolyl group, a benzofuranyl group, or a benzothienyl group, wherein the phenyl group, the naphthyl group, the indolyl group, the benzothiazolyl group, the benzofuranyl group, and the benzothienyl group may be substituted with 1 to 3 selected substituent (s) of the group consisting of a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a halogen atom, a C 1-6 alkoxy group, a C 1-6 haloalkyl group, a C 1-6 haloalkoxy group, a phenyl group, and a group phenoxy (13) The compound or a pharmaceutically acceptable salt thereof as claimed in (11) or (12), wherein X "is the formula: -CH2-. (14) The compound or a pharmaceutically acceptable salt thereof as claimed in any of (11) to (13), wherein W "is a Ci_6 alkylene group.
A preventive agent or a therapeutic agent for allergic diseases such as asthma, atopic dermatitis, and allergic rhinitis including a compound or a pharmaceutically acceptable salt thereof as claimed in any of (1) to (14) as mentioned above as an ingredient active.
Advantageous Effects of the Invention The compound of the present invention has an inhibitory effect on CRTH2.
Way to Carry Out the Invention In the present invention, the Ci-6 alkyl group refers to a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, an n-propyl group, a group isopropyl, an n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, an n-pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group and an n-hexyl group.
The C2-6 alkenyl group refers to an alkenyl group. linear or branched having 2 to 6 carbon atoms, and examples thereof include a vinyl group, a allyl group, a 1-propenyl group, an isopropenyl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, a 1-pentenyl group, a 2-pentenyl group, a 1-hexenyl group, and a 1,3-butadienyl group.
The Ci_6 alkylene group refers to a linear or branched alkylene group having 1 to 6 carbon atoms, and examples thereof include a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group , an ethylidene group, a dimethyl methylene group, and a methyl ethylene group.
Examples of the C2_6 alkylene group including a carbon atom which is also a C3-C-cycloalkyl ring member include a 1,1-ethylene ethylene group, a 1-trimethylene ethylene group, a 1, 1-tetramethylene ethylene group , a 1, 1-pentamethylene ethylene group, a 1,1-ethylene trimethylene group, and a 2,2-ethylene trimethylene group.
Each of the groups mentioned above are shown below.
[Ka 4] The C2-6 alkenylene group refers to a linear or branched alkenylene group having 2 to 6 carbon atoms, and examples thereof include an ethylene group, an propenylene group, and a methylethylene group.
The C3-6 cycloalkyl group refers to a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
The C3-6 cycloalkenyl group refers to a cycloalkenyl group having 3 to 6 carbon atoms, and examples thereof include a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cyclopentadienyl group, and a cyclohexadienyl group.
The C3-6 cycloalkylene group refers to a cycloalkylene group having 3 to 6 carbon atoms, and examples thereof include a cyclopropan-1,1-diyl group, a cyclobutan-1,1-diyl group, a cyclopentan- 1,1-diyl, a cyclohexane-1,1-diyl group, and a cyclohexane-1,4-diyl group.
The aromatic heterocyclic group refers to a monocyclic aromatic heterocyclic group or a fused ring aromatic heterocyclic group that includes one or two heteroatom (s) selected from an oxygen atom, a nitrogen atom, and a sulfur atom in its ring, and examples thereof include a pyridyl group, a pyrimidyl group, a pyridazyl group, a pyrazinyl group, an oxazolyl group, a thiazolyl group, an isoxazolyl group, an isothiazolyl group, an indolyl group, a benzofuranyl group, a benzothienyl group, an imidazolyl group, a thienyl group, a furyl group, a pyrazolyl group, a pyrrolyl group, a group quinoxalyl, a quinolyl group, an isoquinolyl group, a quinazolyl group, a cinnolinyl group, a pyrrolopyridyl group, a naphthyridyl group, an imidazopyridyl group, an indazolyl group, a benzothiazolyl group, a benzoimidazolyl group, and a benzooxazolyl group.
The halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
The Ci_e alkoxy group refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, and examples thereof include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group , an isobutoxy group, a tert-butoxy group, a sec-butoxy group, an n-pentyloxy group, an isopentyloxy group, a neopentyloxy group, a tert-pentyloxy group, and an n-hexyloxy group.
The Ci-6 alkylthio group refers to a linear or branched alkylthio group having 1 to 6 carbon atoms, and examples thereof include a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, a n-group butylthio, an isobutylthio group, a tert-butylthio group, a sec-butylthio group, an n-pentthylthio group, an isopentylthio group, a neopentylthio group, a tert-pentthylthio group, and an n-hexylthio group.
The Ci-6 haloalkyl group refers to a linear or branched alkyl group having 1 to 6 carbon atoms, substituted with halogen atoms, in which the number of halogen atoms is from 3 to 5. Examples thereof include a trifluoromethyl group and a pentafluoroethyl group.
The group Ci_6 haloalkylthio refers to a linear or branched alkylthio group having 1 to 6 carbon atoms, substituted with halogen atoms, in which the preferable number of halogen atoms is 3 to 5. Examples thereof include a group trifluoromethylthio and a pentafluoroethylthio group.
The Ci-6 haloalkoxy group refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, substituted with halogen atoms, in which the preferable number of halogen atoms is from 3 to 5. Examples thereof include trifluoromethoxy group and a pentafluoroethoxy group.
The Ci_6 alkylsulfonyl group refers to a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms, and examples thereof include a methylsulfonyl group, an ethylsulfonyl group, a? - propylsulfonyl group, an isopropylsulfonyl group, a n group -butylsulfonyl, an isobutylsulfonyl group, a tert-butylsulfonyl group, a sec-butylsulfonyl group, an n-pentylsulfonyl group, an isopentylsulfonyl group, a neopentylsulfonyl group, a tert-pentylsulfonyl group, and an n-hexylsulfonyl group.
The C2-7 alkoxycarbonyl group refers to a linear or branched alkoxycarbonyl group having 2 to 7 carbon atoms, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, a group n-butoxycarbonyl, an isobutoxycarbonyl group, a tert-butoxycarbonyl group, a sec-butoxycarbonyl group, an n-pentyloxycarbonyl group, an isopentyloxycarbonyl group, a neopentyloxycarbonyl group, a tert-pentyloxycarbonyl group, and an n-hexyloxycarbonyl group.
The C2-7 alkanoyloxy group refers to a linear or branched alkanoyloxy group having 2 to 7 carbon atoms, and examples thereof include an acetoxy group, a propanyloxy group, an n-butanoyloxy group, and an isobutyroyloxy group. The pharmaceutically acceptable salt refers to a salt with an alkali metal, an alkaline earth metal, ammonium, alkylammonium or the like, or a salt with a mineral acid or an organic acid. Examples thereof include sodium salts, potassium salts, calcium salts, ammonium salts, aluminum salts, triethyl ammonium salts, acetates, propionates, butyrates, formates, trifluoroacetates, maleates, tartarates, citrates, stearates, succinates, Ethyl succinates, lactobionates, gluconates, glucoheptonate, benzoates, methanesulfonates, ethanesulfonates, 2-hydroxyethanesulfonates, benzenesulfonates, para-toluenesulphonates, lauryl sulphates, maleates, aspartates, glutamates, adipates, salts with cysteine, salts with N-acetylcysteines, hydrochlorides, hydrobromides, phosphates, sulphates, iohydrates, nicotinates, oxalates, picrates, thiocyanates, undecanes, salts with polymers of Acrylic acid, and salts with polymeric carboxyvinyl polymers.
The compound of the present invention or a pharmaceutically acceptable salt thereof can be present as a solvate. Examples of the solvate may include hydrates of the compounds and hydrates of the pharmaceutically acceptable salts of the compounds. They are all encompassed in the present invention.
When the compounds of the present invention are used as pharmaceutical preparations, the compounds of the present invention can be formulated by the addition of commonly used excipients, extenders, pH adjusting agents, solubilizers and the like in tablets, granules, pills, capsules. , powders, solutions, suspensions, injectable agents, coating and the like, when using standard techniques. The pharmaceutical preparations can be administered via the oral route or percutaneous route or via the intravenous route.
The compound of the present invention can be administered to an adult patient in a dosage of 0.01 to 100 mg / kg, given as a single dose or in several divided doses per day. This dose can be increased or decreased appropriately depending on the type of diseases, age and body weight, symptoms of the patient and the like.
A preferable aspect of the compound of the present invention includes the following compounds. A compound in which X is the formula: -CH 2 - or the formula: -CO- is preferred. A compound in which Y is the formula: -N 3CO-W-, the formula: -NR3CO-W-0-, the formula: -NR3C02-W-, the formula: -NR3-W-, the formula: - NR3S02-W-, the formula: -NR3CO RW-, the formula: -NR3CO-W-NR4S02-, the formula: -CONR3-W-, the formula: CONR3-W-0-, the formula: -CH2-0 -W-, the formula: -CH2NR3-W-, the formula: -CO R3-WNRCO-, the formula: -OW-, or the formula: -OW-0- is preferred; a compound in which Y is the formula: -NR3CO-W-, or the formula: -CONR3-W- is more preferred; and a compound in which Y is the formula: - HCO-, or the formula: -CONH-W- (W is a Ci-6 alkylene group) is further preferred. A compound in which Z is a benzene ring is preferred. More preferably, X and Y are linked in the para position. A compound in which R1 is a C3-6 cycloalkyl group, a C3-6 cycloalkenyl group, an adamantyl group, an indanyl group, a tetrahydronaphthyl group, a tetrahydroindolyl group, a phenyl group, a naphthyl group, an indolyl group, a benzofuranyl group, a benzothienyl group, a quinolyl group, or an isoquinolyl group, in which the phenyl group, the group Naphthyl, the indolyl group, the benzofuranyl group, the benzothienyl group, the quinolyl group and the isoquinolyl group can be substituted with 1 to 5 substituent (s) selected from the group consisting of a group ie alkyl, a C2_6 alkenyl group, a group C3-6 cycloalkyl, a halogen atom, a Ci-6 alkoxy group, a hydroxy group, a Ci-6 haloal uyl group, a Ci-6 haloalkoxy group, a cyano group, a nitro group, a Ci-6 alkylsulfonyl group , a phenyl group, a benzoyl group, a phenoxy group, the formula: -NR5R6, and the formula: -S02 R7R8 is preferred; a compound in which R1 is a phenyl group, which may be substituted with 1 to 3 substituent (s) selected from the group consisting of a Ci-6 alkyl group, a halogen atom, - a Ci-6 alkoxy group, a Ci_6 haloalkyl group, a Ci-6 haloalkoxy group, a cyano group, a nitro group, a phenyl group, a phenoxy group, and the formula: -NR5R6 is more preferred; and a compound in which R1 is a phenyl group, which is substituted with 1 to 3 halogen atom is further preferred. A compound in which Ra is a carboxy group is preferred. A compound in which both of Rb and Rc are hydrogen atoms is preferred. A compound in which Rd, Re, Rf and Rg are each a hydrogen atom is preferred.
The compounds of the present invention can be synthesized, for example by the production method mentioned below.
Reaction Scheme 1 [Ka 5] (You) In the reaction scheme, Z, Y, R1, Rd, Re, Rf and R9 are the same as defined above, and Hal represents a chlorine atom, a bromine atom and an iodine atom, and L1 represents protecting groups general carboxylic acid, for example, groups described in Protecting Groups in Organic Synthesis (third edition, 1999, PGM Wuts and T. Green) etc., and specifically represents a Ci_6 alkyl group, a benzyl group, a 4-methoxybenzyl group or the like.
Step (1-1): Compound 1-c can be produced by allowing compound 1-a to react with compound 1-b in an ether solvent, such as tetrahydrofuran and dioxane, a halogen solvent such as methylene and chloroform, an aromatic hydrocarbon solvent such as toluene and xylene, or a polar aprotic solvent such as N, N- dimethylformamide, in the presence of bases such as sodium hydride, tert-butoxy potassium and sodium hexamethyldisilazide and furthermore by stirring the product which was reacted in the presence of oxygen.
Step (1-2): This reaction can be carried out by the method described in, for example, Protective Groups in Organic Synthesis (third edition 1999, PGM Wuts and T. 15 Green) etc., or methods similar to this method . Specifically, compound 1-d can be produced by subjecting compound 1-ca hydrolysis with mineral acid such as hydrochloric acid or an inorganic base such as sodium hydroxide and potassium hydroxide in an alcohol solvent such as methanol and ethanol, or in an ether solvent such as tetrahydrofuran and dioxane. When L1 is a benzyl group or a 4-methoxybenzyl group, the compound 1-d can be produced by subjecting the compound 1-ca hydrogenation in an alcohol solvent such as methanol and ethanol, an ether solvent such as tetrahydrofuran and dioxane, a halogen solvent such as methylene chloride and chloroform, an aromatic hydrocarbon solvent such as toluene and xylene, in the presence of a catalyst such as carbon on palladium. When L1 is a 4-methoxybenzyl group, compound 1-d can be produced by deprotection reaction using ceric ammonium nitrate (CAN) or 2,3-dichloro-5,6-dicyan-1,4-benzoquinone (DDQ) .
Stage (1-3): The carboxylic acid chloride obtained by treatment of the compound 1-d with oxalyl chloride, thionyl chloride or the like, in a halogen solvent such as methylene chloride and chloroform or in an aromatic hydrocarbon solvent such as toluene and xylene, is treated with diazomethane, trimethylsilyl diazomethane or the like, in ether solvent such as tetrahydrofuran and dioxane and in a polar solvent such as acetonitrile, or the like. By this, a-diazomethyl ketone can be produced. This compound is allowed to react with silver oxide, silver acetate or the like, in a mixture of solvent and water and an ether solvent such as tetrahydrofuran and dioxane, or in an aqueous solution, and by this the compound can be produced 1-e of the present invention.
Reaction Scheme 2 [Ka 6] In the reaction scheme, Z, Rd, Re, Rf, R9, L1, and Hal are the same as defined above, and Q1 represents the formula: - H-, the formula: -O-, the formula: -C02 -, the formula: -CH20-, the formula: -CH2NH-, and L2 represents protective, general groups of aniline, phenol, carboxylic acid, primary amine, or primary alcohol, for example, groups described in Protective Groups in Organic Synthesis ( third edition, 1999, PGM Wuts and T. Green) etc., and specifically represents a tert-butoxycarbonyl group, a benzyl group, a 4-methoxybenzyl group, a methyl group, an acetyl group, a trimethylsilyl group, a ter- butyldimethylsilyl, or the like, when Q1 is the formula: -NH-, the formula: -0-, the formula: -CH20-, or the formula: -CH2NH-, and represents a Ci-6 alkyl group, a benzyl group , a 4-methoxybenzyl group, or the like, when Q1 is the formula: -C02-.
Step (2-1): Compound 2-b can be produced by using compound 2-a by the same procedure as that used in step (1-1).
Step (2-2): Compound 2-c can be produced by using compound 2-b by the same procedure as that used in step (1-2).
Step (2-3): Compound 2-d can be produced by using compound 2-c by the same procedure as that used in step (1-3).
Stage (2-4): Compound 2-e can be produced at subjecting the compound 2-d to esterification with alkyl alcohol Ci-6, benzyl alcohol, 4-methoxybenzyl alcohol, or the like in the presence of mineral acid such as sulfuric acid. Alternatively, the compound 2-e can be produced by allowing the compound 2-d to react with the alkyl alcohol Ci-6, benzyl alcohol, 4-methoxybenzyl alcohol or the like, in ether solvent such as tetrahydrofuran and dioxane, a solvent of halogen such as methylene chloride and chloroform, an aromatic hydrocarbon solvent such as toluene and xylene, or a polar aprotic solvent such as N, -dimethylformamide, in the presence or absence of a base such as triethylamine and pyridine, and in the presence of a condensing agent such as dicyclohexyl carbodiimide (DCC), l-ethyl-3- (dimethylaminopropyl) -carbodiimide hydrochloride (EDC), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP (registered trademark)), 1-hydroxybenzotriazole hydrate ( HOBt), or the like. Alternatively, compound 2-e can be produced by reacting the carboxylic acid chloride obtained by treating compound 2-d with oxalyl chloride, thionyl chloride, or the like, in a halogen solvent such as methylene chloride. and chloroform or an aromatic hydrocarbon solvent such as toluene and xylene, with C1-6 alkyl alcohol, benzyl alcohol, 4-methoxybenzyl alcohol, or the like. Also, when L1 is a methyl group, compound 2-e can be produced by allowing compound 2-d to react with diazomethane, trimethylsilyl diazomethane, or the like, in an alcohol solvent such as methanol and ethanol. Also, compound 2-e can be produced by allowing compound 2-d to react with iodomethane in an ether solvent such as tetrahydrofuran and dioxane, a halogen solvent such as methylene chloride and chloroform, an aromatic hydrocarbon solvent such such as toluene and xylene, or an aprotic polar solvent such as N, N-dimethylformamide in the presence of a base such as triethylamine, pyridine, potassium carbonate, or the like.
Step (2-5): This reaction can be carried out by the method described in, for example, Protective Groups in Organic Synthesis (third edition 1999, P. G. M. Wuts and T. Green) etc., or methods similar to this method. Specifically, when L2 is a tert-butoxycarbonyl group, a tert-butyl group, a 4-methoxybenzyl group, or a trimethylsilyl group, the compound 2-f can be produced by subjecting the compound 2-e to deprotection reaction using mineral acid such such as hydrochloric acid, acetic acid, trifluoroacetic acid, or the like, in an ether solvent such as tetrahydrofuran and dioxane, a halogen solvent such as methylene chloride and chloroform, or an aromatic hydrocarbon solvent such as toluene and xylene. When L2 is a benzyl group or a 4-methoxybenzyl group, the compound 2-f it can be produced by subjecting compound 2-e to hydrogenation in an alcohol solvent such as methanol and ethanol, an ether solvent such as tetrahydrofuran and dioxane, a halogen solvent such as methylene chloride and chloroform, an aromatic hydrocarbon solvent. such as toluene and xylene, in the presence of a catalyst such as carbon on palladium. When L2 is a trimethylsilyl group or a tert-butyldimethylsilyl group, the 2-f compound can be produced by treating compound 2-e with potassium fluoride., tetrabutylammonium fluoride, or the like. When Q1 is the formula: -O- or the formula: -CH20-, and L2 is a methyl group, the compound 2-f can be produced by treating the compound 2-e with BBr3 in a halogen solvent such as sodium chloride. methylene and chloroform or an aromatic hydrocarbon solvent such as toluene and xylene. When L2 is an acetyl group, the compound 2-f can be produced by subjecting the compound 2-e to hydrolysis with mineral acid such as hydrochloric acid or an inorganic base, such as sodium hydroxide and potassium hydroxide in an alcohol solvent such such as methanol and ethanol or an ether solvent such as tetrahydrofuran and dioxane. When Q1 is the formula: -C02-, the compound 2-f can be produced by the same procedure as that used in step (1-2).
Reaction Scheme 3 [Ka 7] In the reaction scheme, Z, Rd, Re, Rf, Rg, and L1 are the same as defined above and T1 represents the formula: -CO-W-R1, the formula: CO2-W-R1, the formula: -CO-WO-R1, the formula: -SO2-W-R1 or the formula: -CO-W-NR ^ C ^ -R1 (W, R1, and R4 are the same as defined above), U1 represents a general leaving group, for example, a chlorine atom, a bromine atom, an iodine atom, a phenoxy group, an imidazolyl group, a triazolyl group and the like.
Step (3-1): When U1 is a chlorine atom, a bromine atom, an iodine atom, a phenoxy group, an imidazolyl group, or a triazolyl group, the 3-b compound can be produced by allowing the compound 3-a reacts with the compound 2-f1 in an ether solvent such as tetrahydrofuran and dioxane, a halogen solvent such as methylene chloride and chloroform, an aromatic hydrocarbon solvent such as toluene and xylene, or an aprotic polar solvent such as N, N-dimethylformamide, in the presence or absence of a base such as triethylamine and pyridine. Also, compound 3-b can be produced by allowing compound 3-a to react with compound 2-f1 by using a base such as pyridine and triethylamine as a solvent. When T1 is the formula: -CO-W-R1, the formula: -CO-WO-R1 or the formula: -CO-W-NRS02-R1, U1 may be a hydroxyl group, and the compound 3-b may be produced by allowing compound 3-a to react with compound 2-f1 in an ether solvent such as tetrahydrofuran and dioxane, a halogen solvent such as methylene chloride and chloroform, an aromatic hydrocarbon solvent such as toluene and xylene, or an aprotic polar solvent such as N, N-dimethylformamide, in the presence or absence of a base such as triethylamine and pyridine, and in the presence of a condensing agent such as dicyclohexyl carbodiimide (DCC), l-ethyl-3- hydrochloride (dimethylaminopropyl) -carbodiimide (EDC), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP (registered trademark)), 1-hydroxybenzotriazole hydrate (HOBt), or the like.
Step (3-2): Compound 3-c can be produced by using compound 3-b by the same procedure as that used in step (1-2).
Reaction Scheme 4 [Ka 8] In the reaction scheme, Z, R1, Rd, Re, Rf, Rg, W, and L1 are the same as defined above.
Step (4-1): Compound 4-b can be produced by allowing compound 4-a to react with compound 2-f1 in an ether solvent, such as tetrahydrofuran and dxoxane, a halogen solvent such as methylene and chloroform, an aromatic hydrocarbon solvent such as toluene and xylene, or a polar aprotic solvent such as N, N-dimethylformamide.
Step (4-2): Compound 4-c can be produced by using compound 4-b by the same procedure as that used in step (1-2).
Reaction Scheme 5 [Ka 9] In the reaction scheme, Z, Rd, Re, Rf, Rg and L1 are the same as defined above, and Q2 represents the formula: - H-, the formula: -0-, the formula: -CH20-, or the formula: -CH2NH-, T2 represents the formula: -W-R1 or the formula: -WO-R1 (W, R1 are the same as defined above), U2 represents a general leaving group, for example, an chlorine, a bromine atom, an iodine atom, a methansulfonyloxy group, a p-toluenesulfonyloxy group, or the like.
Step (5-1): Compound 5-b can be produced by allowing compound 5-a to react with compound 2-f2 in an ether solvent such as tetrahydrofuran and dioxane, a halogen solvent such as methylene chloride and chloroform, an aromatic hydrocarbon solvent such as toluene and xylene, or a polar aprotic solvent such as N, N-dimethylformamide, in the presence or absence of a base such as triethylamine, pyridine and potassium carbonate. When Q2 is the formula: -O-, U2 can be a hydroxyl group, and the compound 5-b can be produced by allowing the compound 5-a react with compound 2-f2 in an ether solvent such as tetrahydrofuran and dioxane, a halogen solvent such as methylene chloride and chloroform, an aromatic hydrocarbon solvent such as toluene and xylene, or a polar aprotic solvent such as?, ? -dimethylformamide, in the presence of a reagent such as triphenylphosphine and tri-n-butyl fpsphine, diethyl azodicarboxylate and tetramethyl azodicarboxylamide.
Step (5-2): Compound 5-c can be produced by using compound 5-b by the same procedure as that used in step (1-2).
Reaction Scheme 6 [Ka 10] In the reaction scheme, Z, Rd, Re, Rf, R9 and L1 are the same as defined above,. and T3 represents the formula: - -R1, the formula: -W-O-R1 or the formula: -W-NRCO-R1 (W, R1 and R4 are the same as defined above).
Step (6-1): Compound 6-b can be produced by allowing compound 6-a to react with compound 2-f3 in an ether solvent such as tetrahydrofuran and dioxane, a halogen solvent such as methylene chloride and chloroform, an aromatic hydrocarbon solvent such as toluene and xylene, or an aprotic polar solvent such as N, N-dimethylformamide, in the presence or absence of a base such as triethylamine and pyridine, in the presence of a condensing agent such as dicyclohexyl carbodiimide (DCC) ), hydrochloride. l-ethyl-3- (dimethylaminopropyl) -carbodiimide (EDC), benzotriazole-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (PyBOP (registered trademark)), 1-hydroxybenzotriazole hydrate (HOBt), or the like. Alternatively, compound 6-b can be produced by allowing. than the carboxylic acid chloride obtained by treating the compound 2-f3 with oxalyl chloride, thionyl chloride, or the like, in a halogen solvent such as methylene chloride and chloroform, or an aromatic hydrocarbon solvent such as toluene and xylene, react with the compound 6-a in an ether solvent such as tetrahydrofuran and dioxane, a halogen solvent such as methylene chloride and chloroform, or an aromatic hydrocarbon solvent such as toluene and xylene.
Step (6-2): Compound 6-c can be produced by using compound 6-b by the same procedure as that used in step (1-2).
Reaction Scheme 7 [Ka 11] In the reaction scheme, Z, R1, Rd, Re, Rf, R9, L1, and Q2 are the same as defined above.
Step (7-1): Compound 7-a can be produced by treating compound 2-f2 with a reducing agent such as sodium borohydride and lithium aluminum hydride in an alcohol solvent such as methanol and ethanol, a solvent of ether such as tetrahydrofuran and dioxane, a halogen solvent such as methylene chloride and chloroform, or an aromatic hydrocarbon solvent such as toluene and xylene. Compound 7-a can be produced by reacting it with trimethylsilane in an ether solvent such as tetrahydrofuran and dioxane, a halogen solvent such as methylene chloride and chloroform, or an aromatic hydrocarbon solvent such as toluene and xylene in the presence of trifluoroacetic acid, boron trifluoride etherate, or the like. Alternatively, compound 7-a can be produced by hydrogenating compound 2-f2 in a solvent of alcohol such as methanol and ethanol, an ether solvent such as tetrahydrofuran and dioxane, a halogen solvent such as methylene chloride and chloroform, or an aromatic hydrocarbon solvent such as toluene and xylene, in the presence of a catalyst such as carbon on palladium.
Step (7-2): Compound 7-b can be produced by using compound 7-a by the same procedure as in reaction schemes 3 to 5. However, in this case, Y represents the formula: - R3CO -W-, the formula: -NR3CO-W-0-, the formula: -NR3C02-W-, the formula: - R3-W-, the formula: -NR3S02-W-, the formula: -NR3CONR4-W- , the formula: -NR3CO-W-NR S02-, the formula: -CH2-0-W-, the formula: -CH2NR3-W-, the formula: -OW-, or the formula: -OWO- (W, R3, and R4 are the same as defined above).
Reaction Scheme 8 In the reaction scheme, Z, Y, R1, Rd, Re, Rf, Rg, L1, and Hal are the same as defined above, and R15, R16, and R17 represent a Ci_6 alkyl group.
Step (8-1): Compound 8-b can be produced by allowing compound 8-a to react with compound 1-a in an ether solvent such as tetrahydrofuran and dioxane, a halogen solvent such as methylene chloride and chloroform, an aromatic hydrocarbon solvent such as toluene and xylene, or a polar aprotic solvent such as N, N-dimethylformamide, in the presence of a base such as sodium hydride, tert-butoxy potassium and sodium hexamethyldisilazide, and further treatment of the product that was reacted in an aqueous solution of sodium carbonate, potassium carbonate, or the like.
Step (8-2): Compound 8-c can be produced by using compound 8-b by the same procedure as that used in step (1-2).
Step (8-3): Compound 8-d can be produced by using compound 8-c by the same procedure as that used in step (1-3).
Reaction Scheme 9 [Ka 13] © -g) In the reaction scheme, Z, R1, Rd, Re, Rf, R9, R15, R16, R17, Q1, L1, L2, and Hal are the same as defined previously.
Step (9-1): Compound 9-b can be produced by using compound 9-a by the same procedure as that used in step (8-1).
Step (9-2): The compound, 9-c can be produced by using the compound 9-b by the same procedure as that used in step (1-2).
Step (9-3): Compound 9-d can be produced by using compound 9-c by the same procedure as that used in step (1-3).
Step (9-4): Compound 9-e can be produced by using compound 9-d by the same procedure as that used in step (2-4).
Step (9-5): Compound 9-f can be produced by using compound 9-e by the same procedure as that used in step (2-5).
Step (9-6): The compound 9-g can be produced by using the compound 9-f by the same procedure as that used in the reaction schemes 3 to 6. In this case, however, Y represents the formula: -NR3CO-W-, the formula: NR3CO-W-0-, the formula: -NR3C02-W-, the formula: '-NR3-W-, the formula: -NR3S02-W-, the formula: -NR3CONR-W-, the formula: -NR3CO -W- R4S02-, the formula: -CONR3-W-, the formula: -CO R3-W-0-, the formula: -CH2-0- -, the formula: -CH2NR3-W-, the formula: - CONR3-W-NRCO-, the formula: -OW-, or the formula: -0-WO- (W, R3, and R4 are the same as defined above).
Reaction Scheme 10 (10-d) In the reaction scheme, z, Y, R1, Rd, Re, RE, Rg, L1, and Hal are the same as defined above, and Q3 represents an oxygen atom, a sulfur atom, or the formula: NR2- (R2 is the same as defined above).
Step (10-1): Compound 10-b can be produced by allowing compound 10-a to react with compound 1- a in an ether solvent, such as tetrahydrofuran and dioxane, a halogen solvent such as sodium chloride. methylene and chloroform, an aromatic hydrocarbon solvent such as toluene and xylene, or an aprotic polar solvent such as N, N-dimethylformamide, in the presence or absence of a base such as triethylamine, pyridine and potassium carbonate.
Step (10-2): Compound 10-c can be produced by using compound 10-b by the same procedure as that used in step (1-2).
Step (10-3): Compound 10-d can be produced by using compound 10-c by the same procedure as that used in step (1-3).
Reaction Scheme 11 [Ka 15] In the reaction scheme, Z, Y, R1, Rd, Re, Rf, R9, Q1, Q3, L1, L2, and Hal are the same as defined above.
Step (11-1): Compound 11-b can be produced by using compound 11-a by the same procedure as that used in step (10-1).
Step (11-2): Compound 11-c can be produced by using compound 11-b by the same procedure as that used in step (1-2).
Step (11-3): Compound 11-d can be produced by using compound 11-c by the same procedure as that used in step (1-3).
Step (11-4): Compound 11-e can be produced by using compound 11-d by the same procedure as that used in step (2-4).
Step (11-5): Compound 11-f can be produced by using compound 11-e by the same procedure as that used in step (2-5).
Step (11-6): The compound 11-g can be produced by using the compound 11-f by the same procedure as in the reaction schemes 3 to 6. In this case, however, Y represents the formula: NR3CO-W-, the formula: -NR3CO-W-0-, the formula: -NR3C02-W-, the formula: -NR3-W ~, the formula: -NR3S02-W-, the formula: -NR3CONR-W-, the formula: -NR3CO-W-NR4S02-, the formula: -CONR3-W-, the formula: -CONR3-W-0-, the formula: -CH2-0-W-, the formula : -CH2NR3-W-, the formula: -CONR3-W- R4CO-, the formula: -0-W-, or the formula: -0-WO- (W, R3, and R4 are the same as defined above ).
Reaction Scheme 12 [Ka 16] (12-a) Cl2-c) In the reaction scheme, Z, Rd, Re, Rf, Rg, and U2 are the same as defined above; T4 represents the formula: -W-R1, the formula: -CO-W-R1, the formula: -C02-W-R1, the formula: CO-WO-R1 or the formula: -SO2-W-R1 (W , and R1 are the same as defined above); and R18 is a Ci-6 alkyl group.
Step (12-1): Compound 12-c of the present invention can be produced by allowing compound 12-b to react with compound 12-a in an ether solvent such as tetrahydrofuran and dioxane, a halogen solvent such as methylene chloride and chloroform, an aromatic hydrocarbon solvent such as toluene and xylene, and a polar aprotic solvent such as?,? - dimethylformamide, in the presence of a base such as sodium hydride . In addition, a compound of the present invention in which a nitrogen atom is alkylated Ci-e can be produced by carrying out the same reaction using the compound 4-c, the compound 6-c, the compound 5-c in the which Q2 is the formula: -CH2 H-.
Reaction Scheme 13 [Ka 17] In the reaction scheme, Z, Y, R1, Rd, Re, Rf, Rs, R18, L1, L2, and U2 are the same as defined above, Q4 represents the formula: -O-, the formula: -C02 -, or the formula: -CH20-; and Q5 represents the formula: -CH2- or the formula -C0-.
Step (13-1): Compound 13-b can be produced by allowing compound 12-b to react with compound 13-a in an ether solvent such as tetrahydrofuran and dioxane, a halogen solvent such as sodium chloride. methylene and chloroform, a solvent of. aromatic hydrocarbon such as toluene and xylene, and an aprotic polar solvent such as N, N-dimethylformamide, in the presence of a base such as sodium hydride and tert-butoxy potassium.
Step (13-2): Compound 13-c can be produced by using compound 13-b by the same procedure as that used in step (2-5).
Step (13-3): A compound of the present invention 13-d can be produced by using the compound 13-c by the same procedure as in the reaction schemes 5 to 6. In this case, however, Y represents the formula: -OW-, the formula: -OWO-, the formula: -CH2-0-W-, the formula: -CONR3- -, the formula: -CONR3-W-0-, or the formula: -CONR3- W- R4CO- (W, R3, and R4 are the same as defined above).
Diagram of Reaction 14 [Ka 18] (14-d) (L4-e) In the reaction scheme, Z, Y, R1, Rd, Re, Rf, Rg, R18, L1, L2, U2 and Q4 are the same as defined above, and R19 represents a Ci-6 alkyl group.
Step (14-1): Compound 14-c can be produced by using compound 14-b by the same procedure as that used in step (13-1).
Step (14-2): Compound 14-d can be produced by using compound 14-b by the same procedure as that used in step (2-5).
Step (14-3): Compound 14-e can be produced by using compound 14-d by the same procedure as in reaction schemes 5 to 6. In this case, however, Y represents the formula: -OW -, the formula: -OWO-, the formula: -CH2-0-W-, the formula: -CONR3-W- to the formula: CONR3-W-0-, or formula: -CONR3- -R4CO- (W, R3, R4 are the same as defined above).
Reaction Scheme 15 [Ka 19] • Ü5-0 Ú6-e) In the reaction scheme, Z, Y, R1, and L1 are the same as defined above, and R20 and R21 represent a Ci-6 alkoxy group or a hydrogen atom.
Step (15-1): Compound 15-c can be produced by allowing compound 15-b to react with compound 15-a in an ether solvent such as tetrahydrofuran and dioxane, a halogen solvent such as methylene chloride Y chloroformed, an aromatic hydrocarbon solvent such as toluene and xylene, or a polar aprotic solvent such as N, N-dimethylformamide, in the presence or absence of a base such as triethylamine and pyridine, and in the presence of a condensing agent such as dicyclohexyl carbodiimide (DCC), l-ethyl-3- (dimethylaminopropyl) -carbodiimide hydrochloride (EDC), benzotriazole-l-yloxy-tripyrrolidinophosphonium hexafluorophosphate (PyBOP (registered trademark)), hydrated 1-hydroxybenzotriazole (HOBt), or similar.
Alternatively, compound 15-c can be produced by allowing a carboxylic acid chloride obtained by treating compound 15-b with oxalyl chloride, thionyl chloride, or the like, in a halogen solvent such as methylene chloride and chloroform, or an aromatic hydrocarbon solvent such as toluene and xylene with the compound 15-a in an ether solvent such as tetrahydrofuran and dioxane, a halogen solvent such as methylene chloride and chloroform, and an aromatic hydrocarbon solvent such as toluene and xylene.
Step (15-2): Compound 15-d can be produced by treating compound 15-c with phosphorus oxychloride, diphosphorus pentaoxide, polyphosphoric acid, trifluoroacetic anhydride, trifluoromethanesulfonic anhydride, or the like, in a halogen solvent such such as methylene chloride and chloroform, or a hydrocarbon solvent aromatic such as toluene and xylene, in the presence or absence of additives such as 2-chloropyridine.
Step (15-3): The 15-e compound can be produced by treatment. of compound 15-d with. sulfur. Alternatively, the compound · 15-e can be produced by treating the 15-d compound with carbon on palladium or the like in an aromatic hydrocarbon solvent such as toluene and xylene, or an aliphatic hydrocarbon solvent such as decahydronaphthalene.
Step (15-4): Compound 15-f can be produced by using compound 15-e by the same procedure as that used in step (1-2).
Step (15-5): The compound 15-g can be produced by using the compound 15-f by the same procedure as that used in step (1-3).
Reaction Scheme 16 [Ka 20] In the reaction scheme, Z, Y, R1, R20, R21, and L1 are the same as defined above.
Step (16-1): Compound 16-b can be produced by using compound 16-a by the same procedure as that used in step (15-1).
Step (16-2): Compound 16-c can be produced by using compound 16-b by the same procedure as that used in step (15-2).
Step (16-3): Compound 16-d can be produced by using compound 16-c by the same procedure as that used in step (15-3).
Step (16-4): Compound 16-e can be produced by using compound 16-d by the same procedure as that used in step (1-2).
Reaction Scheme 17 Ü7-d) In the reaction scheme, Z, Y, R1, Rd, Re, Rf, R9, and Q5 are the same as defined above.
Step (17-1): Compound 17-b can be produced by allowing compound 17-a to react with aqueous ammonia solution in an ether solvent such as tetrahydrofuran and dioxane, a halogen solvent such as methylene chloride and chloroform, an aromatic hydrocarbon solvent such as toluene and xylene, or a polar aprotic solvent such as?,? - dimethylformamide, in the presence or absence of a base such as triethylamine and pyridine, and in the presence of a condensing agent such as dicyclohexyl carbodiimide (DCC), l-ethyl-3- (dimethylaminopropyl) -carbodiimide hydrochloride (EDC), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP (registered trademark)), 1-hydroxybenzotriazole hydrate (HOBt), and 1,1 '-carbonyl diimidazole (CDI). Alternatively, compound 17-b of the present invention can be produced by allowing a carboxylic acid chloride obtained by treating compound 17-a with oxalyl chloride, thionyl chloride, or the like, in a halogen solvent such such as methylene chloride and chloroform, or an aromatic hydrocarbon solvent such as toluene and xylene with a solution of aqueous ammonia in an ether solvent such as tetrahydrofuran and dioxane, a halogen solvent such as methylene chloride and chloroform, and a solvent hydrocarbon aromatic such as toluene, and xylene.
Step (17-2): Compound 17-c can be obtained by treating compound 17-b with phosphoryl chloride, thionyl chloride, oxalyl chloride, or the like, in a halogen solvent such as methylene chloride and chloroform, or an aromatic hydrocarbon solvent such as toluene and xylene.
Step (17-3): The compound of the present invention 17-d can be produced by allowing the compound 17-c to react with sodium azide in an ether solvent such as tetrahydrofuran and dioxane, a halogen solvent such as chloride of methylene and chloroform, an aromatic hydrocarbon solvent such as toluene and xylene, or a polar aprotic solvent such as?,? - dimethylformamide, in the presence or absence of triethylamine hydrochloride, ammonium chloride or the like.
Reaction Scheme 18 [Ka 22] Ü7-a) &8 ~ a) In the reaction scheme, Z, Y, R1, Rd, Re, Rf, Rg, and Q5 are the same as defined above.
Step (18-1): Compound 18-a of the present invention can be produced by allowing compound 17-to react with hydroxylamine or hydroxylamine hydrochloride in an ether solvent such as tetrahydrofuran and dioxane, a halogen solvent such such as methylene chloride and chloroform, an aromatic hydrocarbon solvent such as toluene and xylene, or an aprotic polar solvent such as N, N-dimethylformamide, in the presence or absence of a base such as triethylamine and pyridine, and in the presence of an agent of condensation such as dicyclohexyl carbodiimide (DCC), l-ethyl-3- (dimethylaminopropyl) -carbodiimide hydrochloride (EDC), benzotriazol-l-yloxy-tripyrrolidinophosphonium hexafluorophosphate (PyBOP (registered trademark)), 1-hydroxybenzotriazole hydrate ( HOBt), 1,1 '-carbonyl diimidazole (CDI). The compound 18-a of the present invention can be produced by the same process by using a reagent such as O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, and O-benzyl hydroxylamine in which a hydroxyl group is protected , instead of using hydroxylamine. Then, the obtained compound is subjected to a deprotection reaction by, for example, a method described in Protective Groups in Organic Synthesis (third edition 1999, PGM Wuts and T. Green) etc., or methods similar to this method, and thus compound 18 -a of the present invention can be produced. Specifically, when the protecting group is a tetrahydropyranyl group, the compound 18a of the present invention can be produced by deprotection reaction using a mineral acid such as hydrochloric acid, acetic acid, trifluoroacetic acid, or the like, in an ether solvent such as tetrahydrofuran and dioxane, a halogen solvent such as methylene chloride and chloroform, or an aromatic hydrocarbon solvent such as toluene and xylene. When the protecting group is a benzyl group, the 18-a compound of the present invention can be produced by hydrogenation in the presence of a catalyst such as palladium on carbon in an alcohol solvent such as methanol and ethanol, an ether solvent such as tetrahydrofuran and dioxane, a halogen solvent such as methylene chloride and chloroform, or an aromatic hydrocarbon solvent such as toluene and xylene.
In the present, the reaction is carried out at a suitable selected temperature of -78 ° C at the boiling points of the solvents to be used in the reaction, and it can be used at room temperature, under pressure, under microwave irradiation , or the like.
Hereinafter, the Examples and Test Examples are shown to describe the present invention in detail.
EXAMPLES Example 1 Acid [1- ( { 4- [(tert-butoxycarbonyl) amin] phenyl} carbonyl) iso-quinolin-4-yl] acetic acid (1) To a solution of 4-aminophenyl-acetonitrile (1.41 g) in ethanol (5 ml), a solution of di-tert-butyl dicarbonate (3.10 g) in ethanol (5 ml) was added, and the mixed solution was added. was stirred at room temperature for two hours. The precipitate was filtered and dried to give [4- (cyanomethyl) phenyl] carbamic acid 1,1-dimethylethyl ester (984 mg) as a colorless solid: XH NMR (600 MHz, CHLOROFORM-d) d ppm 1.52 (s) , 9 H), 3.69 (s, 2 H), 6.49 (br. S., 1 H), 7.22 - 7.26 (m, 2 H), 7.35 - 7.41 (m, 2 H) (2) To a solution of the compound (286 mg) obtained in Example 1- (1) in tetrahydrofuran (2 ml), sodium bis (trimethylsilyl) amide (2.6 ml, 1 M solution) was added in an ice bath. , and the mixed solution was stirred in an ice bath for 30 minutes. A solution of the methyl ester of 1-chloro-isoquinoline-4-carboxylic acid in tetrahydrofuran (3 mL) was added in an ice bath, and stirred at room temperature for 2.5 hours. In addition, the reaction solution was stirred under an atmosphere of oxygen at room temperature for 17 hours. i A saturated solution of ammonium chloride was added, followed by extraction with ethyl acetate, and the organic layer was washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (NH type silica gel (H-DM1020 manufactured by Fuji Silysia Chemical Ltd.) with ethyl acetate / n-hexane = 10 to 30%) to give methyl 1- (. {4- [(tert-butoxycarbonyl)) amin] phenyl.} carbonyl) isoquinoline-4-carboxylic acid methyl (289 mg) as a yellow amorphous substance. NMR ¾ (600 MHz, CHLOROFORM-d) d ppm 1.53 (s, 9 H), 4.07 (s, 3 H), 6.72 (br. S., 1 H), 7.43 - 7.49 (m, 2 H), 7.62 - 7.66 (m, 1 H), 7.83 - 7.89 (m, 3 H), 8.09 - 8.13 (m, 1 H), 8.99 - 9.03 (m, 1 H), 9.20 (s, 1 H) (3) To a suspension of the compound (1.33 g) obtained in Example l- (2) in methanol (30 ml), a 1 N aqueous solution of sodium hydroxide (30 ml) was added, and the mixed solution was stirred at room temperature for 15 hours. The resulting solution was further stirred at 35 ° C for three hours, and acetic acid and water were added thereto. The precipitate was filtered, washed with water and dried to give the acid 1- (. {4- [(tert-butoxycarbonyl) amin] phenyl} carbonyl) iso-quinoline-4-carboxylic acid (1.08 g) as a solid of orange color.
NMR XH (600 MHz, CHLOROFORM-d) d ppm 1.53 (s, 9 H), 6.90 (br. S., 1 H), 7.45 - 7.50 (m, 2 H), 7.65 - 7.69 (m, 1 H) , 7.86 - 7.93 (m, 3 H), 8.12 - 8.15 (m, 1 H), 9.11 - 9.15 (m, 1 H), 9.39 (s, 1 H) (4) To a solution of the compound (1.08 g) obtained in Example l- (3) in chloroform (20 ml), oxalyl chloride (0.709 ml) was added dropwise in an ice bath. The solution was stirred at room temperature for 3.5 hours and evaporated under reduced pressure to remove the solvent. To the resulting crude product, tetrahydrofuran (10 mL) and acetonitrile (10 mL) were added, and dropwise (trimethylsilyl) diazomethane (2.75 mL, 2 M solution) was added in an ice bath, and the resulting solution was stirred for two hours in an ice bath. The resulting solution was evaporated under reduced pressure to remove the solvent, and to the resulting crude product were added water (10 ml), 1,4-dioxane (10 ml), and silver acetate (138 mg) and stirred at 60 ° C. for 30 minutes. The solution was returned at room temperature, and water was added to the solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. To the resulting crude product, methanol (20 ml) was added, (trimethylsilyl) diazomethane (4.54 ml, 2 M solution) was added dropwise, and the solution was stirred at room temperature for 30 minutes. Water was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated under pressure reduced to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH-type silica gel, ethyl acetate / n-hexane = 10 to 35%) to give methyl [1- (. {4- [(tert-butoxycarbonyl)] amino] fe-nyl.} carbonyl) isoquinolin-4-yl] acetate methyl (578 mg) as a yellow solid.
RMN ?? (600 MHz, CHLOROFORM-d) d ppm 1.51 (s, 9 H), 3.72 (s, 3 H), 4.10 (s, 2 H), 6.72 (br. S., 1 H), 7.42 - 7.47 (m , 2 H), 7.58 - 7.63 (m, 1 H), 7.75 - 7.81 (m, 1 H), 7.88 - 7.93 (m, 2 H), 8.02 - 8.06 (m, 1 H), 8.16 - 8.20 (m , 1 H), 8.50 (s, 1 H) (5) To a solution of the compound (1.09 g) obtained in Example l- (4) in methanol (10 ml), a 1.3 N aqueous sodium hydroxide solution (10 ml) was added, and tetrahydrofuran ( 5 ml) and was stirred at room temperature for 1.5 hours. The solution was stirred at 50 ° C for 1.5 hours, and then an aqueous solution of 2N hydrochloric acid was added to the solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was recrystallized (ethyl acetate) to give the title compound (144 mg) as a colorless solid.
[Example 2] Acid { l - [(4- {[[3, 4-dichlorophenyl) carbonyl] amino} phenyl) carbonyl] isoquinolin-4-yl} acetic (1) To a solution of the compound (100 mg) obtained in Example l- (4) in chloroform (1 ml), trifluoroacetic acid (1 ml) was added in an ice bath, and the mixed solution was stirred at room temperature. environment for 1.5 hours. A saturated aqueous solution of sodium hydrogen carbonate was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent to give the. { 1- [(4-aminophenyl) carbonyl] isoquinolin-4-yl} Methyl acetate (91 mg) as a yellow oily substance. RM 1H (600 MHz, CHLOROFORM-d) d ppm 3.73 (s, 3 H), 4.09 (s, 2 H), 6.62-6.66 (m, 2 H), 7.58- 7.62 (m, 1 H), 7.75 - 7.82 (m, 3 H), 8.01 - 8.04 (m, 1 H), 8.15 - 8.18 (m, 1 H), 8.50 (s, 1 H) (2) To a solution of the compound (500 mg) obtained in Example 2- (1) in pyridine (8 ml), 3,4-dichlorobenzoyl chloride (490 mg) was added in an ice bath, and the solution mixed was stirred at room temperature for 13.5 hours. Ethyl acetate, chloroform and water were added to the solution, followed by extraction with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and a saturated saline solution, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove the solvent The resulting crude product was purified by column chromatography (neutral OH-type silica gel, ethyl acetate / n-hexane = 20 to 50%) to give the. { 1- [(4- {[[3, 4-dichlorophenyl) carbonyl] amino} phenyl) carbonyl] isoquinin-4-yl} Methyl acetate (685 mg) as a pale yellow solid.
NMR XH (600 MHz, CHLOROFORM-d) d ppm 3.74 (s, 3 H), 4.12 (s, 2 H), 7.55-7.83 (m, 7 H), 7.97 - 8.08 (m, 4 H), 8.21 - 8.24 (m, 1 H), 8.52 (s, 1 H) (3) To a suspension of the compound (650 mg) obtained in Example 2- (2) in methanol (10 ml), an aqueous solution of 1 N sodium hydroxide (10 ml) was added in an ice bath. In addition, tetrahydrofuran (10 ml) was added at the same room temperature, and the mixture was stirred at room temperature for 30 minutes. Water and hydrochloric acid were added in an ice bath, which was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove the solvent. The resulting crude product was recrystallized (ethanol-water) to give the title compound (489 mg) as a colorless solid.
Compounds of Examples 3 to 126 were obtained by carrying out the same procedures as in Example 2. The structural formulas and NMR values of Examples 1 to 126 are shown in Tables 1-1 to 1-13.
Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Example 127 Acid { 1- [(3- {[[3, 4-dichlorophenyl) carbonyl] amino} phenyl) carbonyl] isoquinolin-4-yl} acetic (1) The same procedure as that used in Example l- (2) was carried out using [3- (cyanomethyl) phenyl] carbamic acid 1, 1-dimethylethyl ester (2.32 g) to give 1- ( {.3- [(tert-butoxycarbonyl) amino] phenyl} carbonyl) iso-quinoline-4-carboxylic acid methyl ester (3.59 g) as a pale yellow amorphous substance.
XH NMR (600 MHz, CHLOROFORM-d) d ppm 1.49 (s, 9 H), 4.07 (s, 3 H), 6.58 (br. S., 1 H), 7.36 - 8.16 (m, 7 H), 8.99 - 9. 04 (m, 1 H), 9.19 (s, 1 H) (2) The same procedure as that used in Example l- (3) was carried out using the compound (3.59 g) obtained in Example 127- (1) to give the acid l- (. {3- [3- (tert-butoxycarbonyl) amino] phenyl} carbonyl) isoquinoline-4-carboxylic acid (3.46 g) as a pale yellow amorphous substance.
NMR ¾ (600 MHz, CHLOROFORM-d) d ppm 1.49 (s, 9 H), 6.79 (br. S., 1 H), 7.39 - 8.18 (m, 7 H), 9.09 - 9.13 (m, 1 H) 9.35 (s, 1 H) (3) The same procedure as the one used in the Example l- (4) was carried out using the compound (3.46 g) obtained in Example 127- (2) to give [1- (. {3- [3-tert-butoxycarbonyl) amino] phenyl]. methyl carbonyl) isoquinolin-4-yl] acetate (1.03 g) as a pale yellow solid.
XH NMR (600 MHz, CHLOROFORM-d) d ppm 1.50 (s, 9 H), 3. 73 (s, 3 H), 4.11 (s, 2 H), 6.56 (br. S., 1 H), 7.40 (s, 8 H), 8.51 (s, 1 H) (4) The same procedure as that used in Example 2- (1) was carried out using the compound (1.03 g) obtained in Example 127- (3) to give the. { l - [(3-aminophenyl) carbonyl] isoquinolin-4-yl} Methyl acetate (534 mg) as a yellow solid.
NMR XH (600 MHz, CHLOROFORM-d) d ppm 3.73 (s, 3 H), 3.79 (br. S., 2 H), 4.10 (s, 2 H), 6.84 - 8.21 (m, 8 H), 8.51 (s, 1 H) (5) The same procedure as that used in Example 2- (2) was carried out using the compound (320 mg) obtained in Example 127- (4) and 3,4-dichlorobenzoyl chloride to give the. { 1- [(3- {[[3, 4-dichloro-phenyl) carbonyl] aminoglyl) carbonyl] isoquinolin-4-yl} Methyl acetate (438 mg) as a pale yellow amorphous substance.
RM ½ (600 MHz, CHLOROFORM-d) d ppm 3.75 (s, 3 H), 4.08 (s, 2 H), 7.33 - 8.43 (m, 12 H), 8.45 s, 1 H) (6) The same procedure as that used in Example 2- (3) was carried out using the compound (438 mg) obtained in Example 127- (5) to give the title compound (178 mg) as a solid pale yellow.
Example 128 Acid { 1- [(4-. {[[(3,4-dichlorophenyl) carbonyl] (methyl) amino.}. Fe-nyl) carbonyl] isoquinolin-4-yl} acetic To a hydride suspension. sodium (48 mg, without oil: 60%) in tetrahydrofuran (4 mL), the compound (190 mg) obtained in Example 2- (3) was added in an ice bath, and the mixture was stirred at room temperature for an hour. To the reaction solution was added iodomethane (0.5 ml), and the mixed solution was stirred at room temperature for three hours. To the solution, 2N aqueous hydrochloric acid solution was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried on anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove the solvent. Diethyl ether was added to the resulting crude product, and the mixture was stirred. The precipitate was filtered and dried to give the title compound (60 mg) as a colorless solid.
Example 129 Acid { 1- [(4- {[[3-dichlorophenyl) sulfonyl] amino} phenyl) carbonyl] isoquinolin-4-yl} acetic (1) To a solution of the compound (320 mg) obtained in Example 2- (1) in pyridine (5 ml), 3,4-dichlorobenzenesulfonyl chloride (368 mg) was added in an ice bath, and the solution mixed was stirred at room temperature for one hour. In addition, 3,4-dichlorobenzenesulfonyl chloride (368 mg) was added thereto, and the resulting solution was stirred at room temperature for one hour. Ethyl acetate was added, the resulting solution was washed with water, and then washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH-type silica gel, ethyl acetate / chloroform = 0 to 40%) to give the. { 1- [(4- {[[3, 4-dichlorophenyl) sulfonyl] amino} phenyl) carbonyl] isoquinolin-4-yl} Methyl acetate (207 mg) as an amorphous substance pale yellow.
RM XH (600 MHz, CHLOROFORM-d) d ppm 3.73 (s, 3 H), 4.11 (s, 2 H), 7.11 - 8.24 (m, 12 H), 8.49 (s, 1 H) (2) The same procedure as that used in Example 2- (3) was carried out using the compound (207 mg) obtained in Example 129- (1) to give the title compound (24 mg) as a solid colorless.
Example 130 Acid { 1- [(4- {[[(3,4-dichlorophenyl) carbamoyl] amino} phenyl) Carbo-nil] isoquinolin-4-yl} acetic (1) To a solution of the compound (320 mg) obtained in Example 2- (1) in N, -dimethylformamide (3 mL), was added a solution of 3,4-dichlorophenyl isocyanate (282 mg) in N, N-dimethylformamide (2 ml) in an ice bath. The mixed solution was stirred at room temperature for one hour. To the resulting solution, ethyl acetate was added, and the resulting solution was washed with water, and then washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was partitioned by column chromatography (neutral OH type silica gel, ethyl acetate / chloroform = 0 to 70%) to give the. { 1- [(4- {[[3, 4-dichlorophenyl) carbamoyl] amino} phenyl) carbonyl] isoquinolin-4-yl} methyl acetate (287 mg) as a colorless solid.
NMR 4i (600 MHz, DMSO-d6) d ppm 3.67 (s, 3 H), 4.29 (s, 2 H), 7.33 - 8.15 (m, 11 H), 8.54 (s, 1 H), 9.19 (br. s., 1 H), 9.42 (br. s., 1 H) (2) The same procedure as the one used in the Example 2- (3) was carried out using the compound (287 mg) obtained in Example 130- (1) to give the title compound (248 mg) as a yellow solid.
Example 131 Acid (L- { [4- ( { [(3,4-Dichlorobenzyl) oxy] carbonyl,} amino) fe-nyl] carbonyl, isoquinolin-4-yl) acetic acid (1) To a solution of the compound (320 mg) obtained in Example 2- (1) in chloroform (5 ml), pyridine (0.324 ml) and phenyl chloroformate (0.189 ml) were added in an ice bath, and The mixed solution was stirred at room temperature for one hour. The resulting solution was evaporated under reduced pressure to remove the solvent to give the fifl4- [(phenoxycarbonyl) mino] phenyl} methyl carbonyl) isoquinolin-4-yl] acetate (440 mg) as a brown oily substance.
NMR XH (600 MHz, CL0R0F0RM0-d) d ppm 3.73 (s, 3 H), 4.11 (s, 2 H), 7.13 - 8.23 (m, 14 H), 8.52 (s, 1 H) (2) To a solution of the compound (440 mg) obtained in Example 131- (1) in tetrahydrofuran (10 ml), were added 3, 4-dichlorobenzyl alcohol (354 mg) and?,? - diisopropyl ethyl amine (0.680 ml), and the mixed solution was refluxed for eight hours. In addition, 3,4-dichlorobenzyl alcohol (354 mg) was added thereto, and the resulting solution was refluxed for eight hours. The solution was returned to room temperature, and ethyl acetate was added thereto. The resulting solution was washed with water, and then washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH-type silica gel, ethyl acetate / n-hexane = 0 to 50%) to give the (l- { [4- ( { [(3 , 4-dichlorobenzyl) oxycarbonyl} amino) phenyl] carbonyl, isoquinolin-4-yl) methyl acetate (280 mg) as a pale yellow amorphous substance.
RM ¾ (600 MHz, CHLOROFOR Od) d ppm 3.73 (s, 3 H), 4.11 (s, 2 H), 5.15 (s, 2 H), 6.99 (br. S., 1 H), 7.20 - 8.25 ( m, .11 H), 8.51 (s, 1 H) (3) The same procedure as that used in Example 2- (3) was carried out using the compound (280 mg) obtained in Example 131- (2) to give the title compound (235 mg) as a solid pale yellow.
Example 132 Acid { 1- [(4-. {[[(3,4-dichlorobenzyl) carbamoyl] amino} phenylpiper-nyl] isoquinolin-4-yl} acetic acid (1) To a solution of the compound (440 mg) obtained in Example 131- (1) in tetrahydrofuran (5 ml), 3,4-dichlorobenzylamine (0.397 ml) was added, and the mixed solution was stirred at 80 ° C. for five hours. The solution was returned to room temperature and ethyl acetate was added thereto. The resulting solution was washed with water and then washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH-type silica gel, methanol / chloroform = 0 to 5%) to give the. { 1- [(4- {[[(3,4-dichlorobenzyl) carbamoyl] amino} phenyl) carbonyl] isoguinolin-4-yl} Methyl acetate (233 mg) as a pale yellow solid.
RM ¾ (600 MHz, DMSO-d6) d ppm 3.66 (s, 3 H), 4.23 -4.34 (m, 4 H), 7.08 (br. S., 1 H), 7.27 - 8.15 (m, 11 H) , 8.53 (s, 1 H), 9.40 (br. S., 1 H) (2) The same procedure as that used in Example 2- (3) was carried out using the compound (233 mg) obtained in Example 132- (1) to give the title compound (60 mg) as a solid yellow.
Example 133 Acid [1- ( { 4- [(3,4-dichlorobenzyl) amino] phenyl} carbonyl) iso-quinolin-4-yl] acetic acid (1) To a solution of the compound (180 mg) obtained in Example 2- (1) in α, β-dimethylformamide (6 ml), 3,4-dichlorobenzyl bromide (162 mg) and potassium carbonate ( 93 mg), and the mixed solution was refluxed for five hours. In addition, 3,4-dichlorobenzyl bromide (162 mg) was added thereto, and the resulting solution was refluxed for one hour. The resulting solution was returned to room temperature, and the ethyl acetate was added to the solution. The resulting solution was washed with water and then washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH-type silica gel, ethyl acetate / n-hexane = 0 to 50%) to give [1- (. {4- [(3,4-dichlorobenzyl) ) amino] phenyl.} carbonyl) isoquinolin-4-yl] methyl acetate (94 mg) as a yellow amorphous substance.
NMR XH (600 MHz, DMS0-d6) d ppm 3.65 (s, 3 H), 4.25 (s, 2 H), 4.38-4.41 (m, 2 H), 6.62-6.66 (m, 2 H), 7.29 - 8.09 (m, 10 H), 8.47 (s, 1 H) (2) The same procedure as that used in Example 2- (3) was carried out using the compound (94). r mg) obtained in Example 133- (1) to give the title compound (53 mg) as a yellow solid.
Example 134 Acid [1- ( { 4- [(3,4-Dichlorobenzyl) oxy] phenyl} carbonyl) isoquinolin-4-yl] acetic acid (1) The same procedure as that used in Example l- (2) was carried out using 4-methoxybenzyl cyanide (2.94 g) to give l - [(4-methoxyphenyl) carbonyl] isoquinoline-4-carboxylate methyl (5.42 g) - RM ?? (600 MHz, CHLOROFORM-d) d ppm 3.88 (S, 3 H), 4.07 (s, 3 H), 6.91 - 6.98 (m, 2 H), 15 7.62 - 8.16 (m, 5 H), 8.99 - 9.03 (m, 1 H), 9.20 (s, 1 H) (2) The same procedure as the one used in the Example I- (3) was carried out using the compound (3.00 g) obtained in Example 134- (1) to give l - [(4-methoxyphenyl) carbonyl] isoquinoline-4-carboxylic acid (1.97 g) as a solid of brown color.
X H NMR (600 MHz, DMSO-d 6) d ppm 3.86 (s, 3 H), 7.05 - 7.10 (m, 2 H), 7.72 - 8.01 (m, 5 H), 8.97 - 9.01 (m, 1 H), 9.10 (s, 1 H), 13.79 (br. S., 1 H) (3) The same procedure as that used in Example l- (4) was carried out using the compound (1.97 g) obtained in Example 134- (2) to give the. { l - [(4- methoxyphenyl) carbonyl] isoquinolin-4-yl} Methyl acetate (1.03 g) as a pale brown solid.
RM XH (600 MHz, CHLOROFORM-d) d ppm 3.73 (S, 3 H), 3:88 (s, 3 H), 4.11 (s, 2 H), 6.92 - 6.97 (m, 2 H), 7.59 - 8.23 (m, 6 H), 8.51 (s, 1 H) (4) To a solution of the compound (1.03 g) obtained in Example 134- (3) in chloroform (30 ml), a solution of boron tribromide (3.70 ml) in chloroform (30 ml) was added dropwise in an ice bath, and the mixed solution was stirred at room temperature for two hours. Methanol was added dropwise to it in an ice bath, and the reaction solution was washed with water and then washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent.
The resulting crude product was purified by column chromatography (neutral OH type silica gel, 0 to 5% methanol / chloroform) to give the. { l - [(4-hydroxyphenyl) carbonyl] isoquinolin-4-yl} Methyl acetate (463 mg) as a yellow solid.
NMR XH (600 MHz, CL0R0F0RM0-d) d ppm 3.74 (s, 3 H), 4.12 (s, 2 H), 6.71 - 6.76 (m, 2 H), 7.31 - 8.19 (m, 7 H), 8.49 ( S, 1 H) (5) To a solution of the compound (200 mg) obtained in Example 134- (4) in N, N-dimethylformamide (5 ml), were added 3, 4-dichlorobenzyl bromide (0.111 ml) and potassium carbonate (103 mg), and the mixed solution was stirred at 80 ° C for four hours. Ethyl acetate was added thereto, and the resulting solution washed with water and then washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH-type silica gel, ethyl acetate / n-hexane = 0 to 50%) to give [1- (. {4- [(3,4-dichlorobenzyl) methyl) oxy] phenyl.} carbonyl) isoquinolin-4-yl] acetate (70 mg) as a yellow amorphous substance.
NMR XH (600 MHz, CHLOROFORM-d) d ppm 3.73 (s, 3 H), 4.11 (s, 2 H), 5.09 (s, 2 H), 6.97 - 7.02 (m, 2 H), 7.23 - 8.23 ( m, 9 H), 8.50 (s, 1 H) (6) The same procedure as that used in Example 2- (3) was carried out using the compound (70 mg) obtained in Example 134- (5) to give the title compound (33 mg) as a substance colorless amorphous The structural formalities and NMR values of the Examples 127 to 134 are shown in Table 2.
[Ka 24] Example 135 Acid { 1- [(4- { [2- (4-chlorophenyl) ethyl] carbamoyl.} Phenyl) Carbo-nil] isoquinolin-4-yl) acetic (1) The same procedure as that used in Example l- (2) was carried out using tert-butyl 4- (cyanomethyl) benzoate (10.3 g) to give l-. { [4- (tert-butoxycarbonyl) phenyl] carbonyl} methyl isoquinoline-4-carboxylate (11.6 g) as a yellow oily substance.
RM XH (600 MHz, CHLOROFORM-d) d ppm 1.61 (s, 9 H), 4.08 (s, 3 H), 7.65 - 9.04 (m, 8 H), 9.20 (s, 1 H) 5 (2) The same procedure as that used in Example l- (3) was carried out using the compound (11.5 g) obtained in Example 135- (1) to give the acid l-. { [4- (tert-butoxycarbonyl) phenyl] carbonyl} Isoquinoline-4-carboxylic acid (9.47 g) as a colorless solid. 1 H-NMR (600 MHz, DMSO-d 6) d ppm 1.56 (s, 9 H), 7.45 -9.01 (m, 8 H), 9.11 (s, 1 H), 13.83 (br. S., 1 H) (3) The same procedure as that used in Example l- (4) was carried out using the compound (9.47 g) obtained in Example 135- (2) to give 4-. { [4- (2-methoxy-2-oxoethyl) isoquinolin-1-yl] carbonyl} tert-butyl benzoate (4.09 g) as an orange colored amorphous substance.
X H NMR (600 MHz, CHLOROFORM-d) d ppm 1.61 (s, 9 H), 3.73 (s, 3 H), 4.12 (s, 2 H), 7.64 - 8.33 (m, 8 H), 8.52 (s, 1 HOUR) (4) To a solution of the compound (4.09 g) obtained in Example 135- (3) in chloroform (200 ml), trifluoroacetic acid (33 ml) was added, and the mixed solution was stirred at 50 ° C for one hour . The solution was returned to room temperature, and water was added to the solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent to give the acid 4-. { [4- (2-methoxy-2-oxoethyl) isoquinolin-1-yl] carbonyl} benzoic (3.39 g) as a yellow solid.
NMR ¾ (600 MHz, CHLOROFORM-d) d ppm 3.74 (s, 3 H), 4.14 (s, 2 H), 7.66 - 8.39 (m, 8 H), 8.54 (s, 1 H) (5) To a solution of the compound (1.20 g) obtained in Example 135- (4) in chloroform (23 ml), oxalyl chloride (0.457 ml) and?,? - dimethylformamide (1 drop) were added, and the Mixed solution was stirred at room temperature for one hour. The reaction solution was removed by evaporation under reduced pressure. To the resulting crude product (316 mg), chloroform (3 mL), 2- (4-chlorophenyl) ethyl amine (267 mg) and pyridine (0.139 mL) were added, and the mixed solution was stirred at room temperature for 14 hours. The reaction solution was washed with a saturated solution of ammonium chloride. The organic layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by chromatography column (NH-type silica gel, ethyl acetate / n-hexane = 0 to 50%, chloroform), and recrystallized (n-hexane / ethyl acetate) to give the. { 1- [(4- {[2- (4-chlorophenyl) ethyl] carbamoyl} phenyl) carbonyl] isoquinolin-4-yl} Methyl acetate (188 mg) as a colorless solid.
NMR XH (600 MHz, CHLOROFOR Od) d ppm 2.90 - 2.95 (m, 2 H), 3.68 - 3.76 (m, 5 H), 4.12 (s, 2 H), 6.13 - 6.20 (m, 1 H), 7.13 - 8.35 (m, 12 H), 8.51 (s, 1 H) (6) To a solution of the compound (188 mg) obtained in Example 135- (5) in tetrahydrofuran (3 mL), an aqueous solution of 1 N sodium hydroxide (1.5 mL) was added in an ice bath, and The mixed solution was stirred at room temperature for one hour. Water and 1N hydrochloric acid aqueous solution were added in an ice bath, followed by extraction with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was recrystallized (ethanol-water) to give the title compound (143 mg) as a colorless solid.
Compounds of Examples 136 to 140 were obtained by carrying out the same procedures as in Example 135. The structural formulas and NMR values of Examples 135 to 140 are shown in Table 3.
[Ka 25] Table 3 Example 141 Acid [1- ( { 4- [2- (4-chlorophenyl) ethoxy] phenyl} carbonyl) isoquinolin-4-yl] acetic acid (1) To a solution of the compound (100 mg) obtained in Example 134- (4) in tetrahydrofuran (2 ml), 2- (4-chlorophenyl) ethanol, tri-n-butyl phosphine (0.116 ml) and tetramethyl azodicarboxamide (80 mg). The mixed solution was stirred at room temperature for 18 hours. To the reaction solution, water was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH-type silica gel, ethyl acetate / n-hexane = 10 to 50%) to give [1- (. {4- [2- (4-chlorophenyl) ) ethoxy] phenyl.} carbonyl) isoquinolin-4-yl] methyl acetate (41 mg) as a colorless oily substance.
NMR XH (600 MHz, CHLOROFORM-d) d ppm 3.09 (t, J = 6.8 Hz, 2 H), 3.73 (s, 3 H), 4.10 (s, 2 H), 4.22 (t, J = 6.8 Hz, 2 H), 6.89 - 8.52 (m, 13 H) (2) The same procedure as the one used in the Example 135- (6) was carried out using the compound (38 mg) obtained in Example 141- (1) to give the title compound (35 mg) as a colorless amorphous substance.
To carry out the same procedure as in Example 141, the compounds of Examples 142 and Example 143 They were obtained.
E emplo 144 Acid { 1- [(4-benzyl phenyl) carbonyl] isoquinolin-4-yl} acetic (1) The same procedure as that used in the Example I- (2) was carried out using 4-benzyl phenyl acetonitrile (2.06 g) to give methyl 1- [(4-benzyl phenyl) carbonyl] isoquinoline-4-carboxylate (1.82 g).
XH NMR (600 MHZ, CHLOROFORM-d) d ppm 4.05 (s, 2 H), 4.07 (s, 3 H), 7.13 - 9.05 (m, 13 H), 9.19 (s, 1 H) (2) The same procedure as that used in Example l- (3) was. carried out using the compound (1.81 g) obtained in Example 144- (1) to give l - [(4-benzyl phenyl) carbonyl] isoquinoline-4-carboxylic acid (1.10 g).
· XH NMR (600 MHz, CHLOROFORM-d) d ppm 4.03 (s, 2 H), 7. 07 - 9.14 (m, 13 H), 9.34 (s, 1 H) (3) The same procedure as that used in Example l- (4) was carried out using the compound (1.10 g) obtained in Example 144- (2) to give the. { 1- [(4-benzyl phenyl) carbonyl] isoquinolin-4-yl} Methyl acetate (550 mg).
XH NMR (600 MHz, CHLOROFORM-d) d ppm 3.72 (s, 3 H), 4.05 (s, 2 H), 4.10 (s, 2 H), 7.15 - 8.26 (m, 13 H), 8.50 (s, 1 HOUR) (4) The same procedure as that used in Example 135- (6) was carried out using the compound (538) mg) obtained in Example 144- (3) to give the title compound (35 mg) as a pale yellow amorphous substance.
By carrying out the same procedure as in Example 144, a compound of Example 145 was obtained.
Example 146 Acid { 1- [(4- { [2- (4-chlorophenyl) ethoxymethyl] phenyl) carbonyl] iso-quinolin-4-yl} acetic (1) To a solution of 4-chlorobenzyl alcohol (4.10 g) in?,? -dimethylformamide (110 ml), sodium hydride (60 to 72%, 952 mg) was added in an ice bath, and the mixed solution It was agitated for 30 minutes. Then, to the resulting solution, the methyl ester of 4- (bromomethyl) benzoic acid (5.00 g) was added, and the mixed solution was stirred at room temperature for three hours. To the resulting solution, ethyl acetate was added. The resulting solution was washed with water and with a saturated saline solution, sequentially, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH-type silica gel, ethyl acetate / n-hexane = 5 to 9%) to give 4-. { [2- (4-chlorophenyl) ethoxy] methyl} methyl benzoate (5.25 g).
NMR XH (600 MHz, CHLOROFOR Od) d ppm 2.90 (t, J = 6.6 Hz, 2 H), 3.68 (t, J = 6.6 Hz, 2 H), 15 3.91 (s, 3 H), 4.56 (s, 2 H), 7.11 - 7.37 (m, 6 H), 7.92 - 8.05 (m, 2 H) (2) To a solution of the compound (2.50 g) obtained in Example 146- (1) in tetrahydrofuran (40 ml), lithium aluminum hydride (467 mg) was added in an ice bath, and the mixed solution was stirred for 15 minutes, and then stirred at room temperature for two hours. Water was added to the solution in an ice bath, and then an aqueous solution of 2.5 N sodium hydroxide was added. The solution was stirred for 30 minutes, and then stirred at room temperature for 1.5 hours. The reaction solution was filtered through celite, and the filtrate was removed by evaporation under reduced pressure. The resulting crude product was purified by column chromatography (neutral OH-type silica gel, ethyl acetate / n-hexane = 9 to 15%) to give (4- { [2- (4-chlorophenyl) ethoxy] methyl.} phenyl) methanol (2.24 g).
H NMR (600 MHz, CHLOROFORM-d) d ppm 1.62 (t, J = 6.0 Hz, 1 H), 2.88 (t, J = 6.9 Hz, 2 H), 3.66 (t, J = 6.9 Hz, 2 H), 4.50 (s, 2 H), 4.69 (d, J = 6.0 Hz, 2 H), 7.02 - 7.44 (m, 8 H) (3) To a solution of the compound (2.24 g) obtained in Example 146- (2) in chloroform (40 ml), triethylamine (1.12 ml) was added, and thionyl chloride (0.646 ml) was added in a water bath. ice. Then, the mixed solution was stirred at room temperature for one hour. Water was added thereto, followed by extraction with chloroform. The organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and evaporated under pressure. reduced to remove the solvent. To a solution of the resulting crude product in DMSO (27 ml), sodium cyanide (436 mg) was added, and the mixed solution was stirred at room temperature for one hour, and then stirred at 60 ° C for 30 minutes. Water was added to the solution, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH-type silica gel, ethyl acetate / n-hexane = 15 to 25%) to give (4- { [2- (4-chlorophenyl) ethoxy] methyl.} phenyl) acetonitrile (1.62 g).
NMR XH (600 MHz, CHLOROFORM-d) d ppm 2.89 (t, J = 6.9 Hz, 2 H), 3.66 (t, J = 6.9 Hz, 2 H), 3.74 (s, 2 H), 4.50 (s, 2 H), 7.04 - 7.34 (m, 8 H) (4) The same procedure as that used in the Example 1 - (2) was carried out using the compound (1.42 g) obtained in Example 146- (3) to give 1- [(4- {[2- (4-chlorophenyl) ethoxy] methyl} phenyl) carbonyl] isoquinoline-4-carboxylic acid methyl ester (950 mg).
NMR ½ (600 MHz, CHLOROFORM-d) d ppm 2.84 - 2.94 (m, 2 H), 3.64 - 3.71 (m, 2 H), 4.08 15 (s, 3 H), 4.56 (s, 2 H), 7.11 - 8.17 (m, 11 H), 9.02 (d, J = 8.7 Hz, 1 H), 9.20 (s, 1 H) (5) The same procedure as that used in Example 135- (6) was carried out using the compound (951 mg) obtained in Example 146- (4) to give the acid l - [(4- { [2- (4-chlorophenyl) ethoxy] methyl} phenyl) carbonyl] isoquinoline-4-carboxylic acid (950 mg).
NMR XH (600 MHz, CHLOROFORM-d) d ppm 2.82-2.95 (m, 2 H), 3.59 - 3.77 (m, 2 H), 4.59 (s, 2 H), 7.00 - 9.19 (m, 12 H), 9.38 (s, 1 H) (6) The same procedure as that used in Example l- (4) was carried out using the compound (674 mg) obtained in Example 146- (5) to give the. { 1- [(4- {[2- (4-chlorophenyl) ethoxylmethyl} phenyl) carbonyl] isoquinolin-4-yl} Methyl acetate (260 mg).
NMR ½ (600 MHz, CHLOROFORM-d) d ppm 2.89 (t, J = 6.6 Hz, 2 H), 3.68 (t, J = 6.6 Hz, 2 H), 3.73 (s, 3 H), 4.11 (s, 2 H), 4.58 (s, 2 H), 7.12 - 8.27 (m, 12 H), 8.52 (s, 1 H) (7) The same procedure as that used in Example 135- (6) was carried out using the compound (253 mg) obtained in Example 146- (6) to give the title compound (140 mg) as a substance amorphous pale yellow.
Example 147 Acid chlorohydrate. { 1- [(4-. {[[(4-chlorobenzyl) amino] methyl}. Fe-nyl) carbonyl] isoquinolin-4-yl} acetic (1) To a solution of the methyl 4-formyl benzoic acid (10.0 g) in chloroform (300 ml), 4-chlorobenzylamine (11.2 g) was added, and the mixed solution was stirred for 15 minutes. Then, to the resulting solution, it was added Sodium triacetoxyborohydride (16.8 g), and the mixed solution was stirred at room temperature for two hours. To the resulting solution, acetic acid (10.5 ml) was added, and the solution was stirred for four hours. Saturated sodium bicarbonate) water was added, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure to remove the solvent, and the resulting crude product was purified by column chromatography (neutral OH-type silica gel, ethyl acetate / n-hexane = 15 to 50). %) to give the 4-. { [(4-chlorobenzyl) amino] methyl} methyl benzoate (13.8 g).
NMR XH (600 MHz, CHLOROFORM-d) d ppm 3.77 (s, 2 H), 3.84 (s, 2 H), 3.91 (s, 3 H), 7.24 - 7.33 (m, 4 H), 7.41 (d, J = 8.7 Hz, 2 H), 7.97 - 8.04 (m, 2 H) (2) To a solution of the compound (13.8 g) obtained in Example 147- (1) in chloroform (239 ml), di-tert-butyl dicarbonate (12.5 g) was added, and 4-dimethyl amino pyridine was added. (5.80 g) in an ice bath. The mixed solution was stirred at room temperature for three hours, and the reaction solution was removed by evaporation under reduced pressure. The resulting crude product was purified by column chromatography (neutral OH-type silica gel, ethyl acetate / n-hexane = 3 to 7%) to give 4-. { [(tert-butoxycarbonyl) (4-chlorobenzyl) amino] methyl} methyl benzoate (12.9 g).
NMR XH (600 MHz, CHLOROFORM-d) d ppm 1.47 (s, 9 H), 3.92 (s, 3 H), 4.23 - 4.55 (m, 4 H), 7.05 - 7.33 (m, 6 H), 7.96 - 8.03 (m, 2 H) (3) The same procedure as that used in Example 146- (2) was carried out using the compound (2.00 g) obtained in Example 147- (2) to give tert-butyl (4-chlorobenzyl) [4- (hydroxymethyl) benzyl] carbamate (1-79 g).
NMR B. (600 MHz, CHLOROFORM-d) d ppm 1.49 (s, 9 H), 1.63 - 1.67 (m, 1 H), 4.25 - 4.45 (m, 4 H), 4.66 - 4.73 (m, 2 H) , 7.07 - 7.35 (m, 8 H) (4) The same procedure as that used in Example 146- (3) was carried out using the compound (1.70 g) obtained in Example 147- (3) to give (4-chlorobenzyl) [4- (cyanomethyl) benzyl] tert-butyl carbamate (1.30 g) · 1 H NMR (600 MHz, CHLOROFORM-d) d ppm 1.49 (s, 9 H), 3.74 (s, 2 H), 4.22 - 4.48 (m, 4 H), 7.06 - 7.32 (m, 8 H) (5) The same procedure as that used in Example l- (2) was carried out using the compound (1.30 g) obtained in Example 147- (4) to give 1- [(4- {[[ (tert-butoxycarbonyl) (4-chlorobenzyl) amino] methyl) phenyl) carbonyl] isoquinoline-4-carboxylic acid methyl ester (750 mg).
X H NMR (600 MHz, CHLOROFORM-d) d ppm 1.48 (s, 9 H), 4.08 (s, 3 H), 4.26 - 4.53 (m, 4 H), 7.04 - 8.22 (m, 11 H), 8. 98 - 9.05 (m, 1 H), 9.20 (s, 1 H). (6) The same procedure as that used in Example 135- (6) was carried out using the compound (749 mg) obtained in Example 147- (5) to give the acid l - [(4- {. [(tert-butoxycarbonyl) (4-chlorobenzyl) aminolmethyl] phenyl) carbonyl] isoquinoline-4-carboxylic acid (684 mg).
H NMR (600 MHz, CHLOROFORM-d) d ppm 1.47 (br. S., 9 H), 4.21 - 4.58 (m, 4 H), 7.05 - 8.22 (m, 11 H), 9.09 - 9.17 (m, 1 H), 9.37 (s, 1 H) (7) The same procedure as the one used, in the Example I- (4) was carried out using the compound (681 mg) obtained in Example 147- (6) to give the. { 1- [(4-. {[[(Tert-butoxycarbonyl) (4-chlorobenzyl) aminolmethyl] phenyl) carbonyl] isoquinolin-4-yl} Methyl acetate (230 mg).
XH NMR (600 MHz, CHLOROFORM-d) d ppm 1.48 (s, 9 H), 4. 12 (s, 2 H), 4.25 - 4.51 (m, 4 H), 7.06 - 8.30 (m, 12 H), 8.52 (s, 1 H) (8) The same procedure as that used in Example 135- (6) was carried out using the compound (223 mg) obtained in Example 147- (7) to give the acid. { l - [(4- {[[(tert-butoxycarbonyl) (4-chlorobenzyl) aminolmethyl} phenyl) carbonyl] isoquinolin-4-yl} acetic acid (170 mg).
NMR ½ (600 MHz, CHLOROFORM-d) d ppm 1.47 (s, 9 H), 4.12 (s, 2 H), 4.23 - 4.54 (m, 4 H), 25 6.99 - 8.32 (m, 12 H), 8.52 (s, 1 H) (9) To a solution of the compound (168 mg) obtained in Example 147- (8) in ethyl acetate (1 mL), 4 N hydrochloric acid-ethyl acetate (1 mL) was added, and the mixed solution was stirred at room temperature for 15 hours. The produced solid was filtered to give the title compound (120 mg) as a colorless solid.
The structural formulas and R values of Examples 141 to 147 are shown in Table 4.
[Ka 26] Table 4 E emplo 148 [1- (4-. {[[(3,4-Dichlorophenyl) carbonyl] amino] benzyl) isoquinolin-4-yl] acetic acid (1) To a solution of the compound (500 mg) obtained in Example 2- (1) in tetrahydrofuran (10 ml) -methanol (3 ml), sodium borohydride (173 mg) was added in an ice bath, and The mixed solution was stirred for 15 minutes. In addition, sodium borohydride (177 mg) was added to the solution, and the mixed solution was stirred for 30 minutes in an ice bath. In addition, sodium borohydride (354 mg) was added three times every 30 minutes in an ice bath. A saturated aqueous solution of ammonium chloride was added, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. To a solution of the resulting crude product in chloroform (7 ml), triethylsilane (1.5 ml) and trifluoroacetic acid (1.5 ml) were added, and the mixed solution was stirred at 60 ° C for 14 hours. To the solution was added a saturated aqueous solution of hydrogen carbonate of sodium, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (NH type silica gel, ethyl acetate / n-hexane = 40 to 60%) to give [1- (4-amino-benzyl) isoguinolin-4-yl] -acetate. methyl (165 mg) as a colorless solid.
NMR ½ (600 MHz, CHLOROFORM-d) d ppm 3.53 (br. S., 2 'H), 3.69 (s, 3 H), 3.99 (s, 2 H), 4.54 (s, 2 H), 6.56 - 6.61 (m, 2 H), 7.05 - 7.09 (m, 2 H), 7.51 -7.56 (m, 1 H), 7.66 -7.70 (m, 1 H), 7.92 - 7.95 (m, 1 H), 8.18 - 8.22 (m, 1 H), 8.39 (s, 1 H) (2) To a solution of the compound (190 mg) obtained in Example 148- (1) in pyridine (3 mL), 3,4-dichlorobenzoyl chloride (195 mg) was added in an ice bath, and the solution mixed was stirred at room temperature for 14 hours. A saturated aqueous solution of sodium hydrogencarbonate was added, followed by extraction with ethyl acetate. The organic layer was washed with dilute hydrochloric acid to which a saturated aqueous solution of sodium hydrogencarbonate was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (acid OH-type silica gel, ethyl acetate / n- hexane 30 to 60%) to give methyl [1- (4- {[[(3,4-dichlorophenyl) carbonyl] amino} benzyl) isoquinolin-4-yl] acetate (210 mg) as a solid pale coffee RM ¾ (600 MHz, CHLOROFORM-d) d ppm 3.69 (s, 3 H), 4.00 (s, 2 H), 4.64 (s, 2 H), 7.26 - 7.28 (m, 2 H), 7.45 - 7.72 ( m, 7 H), 7.90 - 7.97 (m, 2 H), 8.13- 8.17 (m, 1 H), 8.40 (s, 1 H) (3) To a solution of the compound (200 mg) obtained in Example 148- (2) in tetrahydrofuran (4 mL) -methanol (4 mL), an aqueous solution of 1 N sodium hydroxide (6 mL) in an ice bath, and the mixed solution was stirred in an ice bath for 20 minutes. Water and acetic acid were added to it, and the precipitate was filtered, washed with water, and then dried. The resulting crude product was recrystallized (ethanol-water) to give the title compound (165 mg) as a colorless solid.
Example 149 Acid (l- { 4- [2- (4-chlorophenyl) ethoxy] benzyl]. Isoquinolin-4-yl) acetic acid (1) The same procedure as that used in Example 148- (1) was carried out using the compound (1.00 g) obtained in Example 134- (3) to give [1- (4-methoxybenzyl) isoquinoline- 4-yl] methyl acetate (621 mg) as a pale yellow solid.
NMR XH (600 MHz, CHLOROFORM-d) d ppm 3.69 (s, 3 H), 3.74 (s, 3 H), 4.00 (s, 2 H), 4.60 (s, 2 H), 6.76 - 8.42 (m, 9 H) (2) To a solution of the compound (678 mg) obtained in Example 149- (1) in chloroform (20 ml), a solution of boron tribromide (1.09 ml) in chloroform (10 ml) was added dropwise to -50 ° C, and the mixed solution was stirred in an ice bath for one hour. Methanol was added dropwise to it in an ice bath, and saturated sodium bicarbonate-water was added, followed by extraction with chloroform. The solution was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH type silica gel, ethyl acetate / n-hexane = 20 to 60%) to give [1- (4-hydroxybenzyl) isoquinolin-4-yl] acetate of methyl (418 mg) as a colorless solid.
½ NMR (600 MHz, CHLOROFORM-d) d ppm 3.69 (s, 3 H), 4.00 (s, 2 H), 4.58 (s, 2 H), 6.66 - 8.40 (m, 9 H) (3) The same procedure as that used in Example 141- (1) was carried out using the compound (120 mg) obtained in Example 149- (2) to give the (1-4. - (Methyl 4-chlorophenyl) ethoxy] benzyl] -isoquinolin-4-yl) acetate (95 mg) as a colorless solid.
XH NMR (600 MHz, CHLOROFORM-d) d ppm 3.00 (t, J = 6.9 Hz, 2 H), 3.69 (S, 3 H), 3.99 (s; 2 H), 4.08 (t, J = 6.9 Hz, 2 H), 4.58 (s, 2 H), 6.73 - 8.41 (m, 13 H) (4) To a solution of the compound (83 mg) obtained in Example 149- (3) in tetrahydrofuran (2 ml), an aqueous solution of 1 N sodium hydroxide (1 ml) was added, and the mixed solution was stirred at room temperature for 23 hours. A saturated aqueous solution of ammonium chloride was added thereto, and acetic acid was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. To the resulting crude product, diethyl ether was added, and the mixture was stirred at room temperature for 14 hours. The produced solid was filtered to give the title compound (58 mg) as a colorless solid.
By the same procedure as in Example 149, the compounds of Examples 150 and 151 were obtained.
Example 152 Acid [1- (4-. {[2- (4-chlorophenyl) ethyl] sulfamoyl} benzyl) isoquinolin-4-yl] acetic acid (1) To a solution of 2- (4-chlorophenyl) ethylamine (2.83 g) and triethylamine (1.46 ml) in tetrahydrofuran (50 ml), 4- (bromomethyl) benzenesulfonyl chloride (1.63 g) was added, and the solution mixed was stirred at room temperature by a hour. Ethyl acetate was added thereto, and the solution was washed with a saturated solution of ammonium chloride and then washed with water. The organic layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH-type silica gel, ethyl acetate / n-hexane = 10 to 30%) to give 4- (bromomethyl) -N- [2- (4-chlorophenyl) ethyl] benzenesulfonamide (2.04 g) as a colorless solid.
XH NMR (600 MHz, CHLOROFORM-d) d ppm 2.67-2.82 (m, 2 H), 3.12 - 3.33 (m, 2 H), 4.38 (t, J = 6.2 Hz, 1 H), 4.50 (s, 2 H), 6.93 - 7.80 (m, 8 H) (2) To a solution of the compound (927 mg) obtained in Example 152- (1) in toluene (12 ml), tri-n-butyl phosphine (0.883 ml) was added, and the mixed solution was stirred at 60 °. C for 30 minutes. The reaction solution was removed by evaporation under reduced pressure, and to a solution of the resulting crude product in chloroform (10 ml), n-hexane (200 ml) was added dropwise. The solution was stirred at room temperature for one hour. After decanting, tributyl (4- {[2- (4-chlorophenyl) ethyl] sulfamoyl} benzyl) phosphonium bromide (1.37 g) was obtained as a colorless amorphous substance.
XH NMR (600 MHz, CHLOROFORM-d) d ppm 0.88 - 0.96 (m, 9 H), 1.40 - 1.52 (m, 12 H), 2.31 - 2.40 (m, 6 H), 2.85 (t, J = 7.3 Hz , 2 H), 3.14 - 3.20 (m, 2 H), 4.46 - 4.58 (m, 2 H), 5. 90 - 5.97 (m, 1 H), 7.07 - 7.24 (m, 4 H), 7.57 - 7.85 (m, 4 H) (3) To a solution of the compound (1.02 g) obtained in Example 152- (2) and methyl ester of 1-chloro-isoquinoline-4-carboxylic acid (381 mg) in tetrahydrofuran (9 ml), was added dropwise. sodium bis (trimethylsilyl) amide drop (2.72 ml, 1.9 M solution) at -30 ° C, and the solution was stirred at room temperature for two hours. In addition, the solution was stirred at 50 ° C for one hour, and then an aqueous solution of 1 M sodium carbonate (3.44 ml) was added thereto, and the solution was stirred at 50 ° C for two hours. Then ethyl acetate was added thereto, and the solution was washed with a saturated aqueous solution of ammonium chloride, and then washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH-type silica gel, ethyl acetate / n-hexane = 10 to 50%) to give 1- (4- { [2- (4-chlorophenyl)) ethyl] sulfamoyl.} benzyl) iso-quinoline-4-carboxylate (124 mg) as a pale yellow solid.
RM ½ (600 MHz, DMSO-d6) d ppm 2.57-2.63 (m, 2 H), 2.88-2.95 (m, 2 H), 3.96 (s, 3 H), 4.83 (s, 2 H), 7.07 - 8.83 (m, 13 H), 9.00 (s, 1 H) (4) To a solution of the compound (169 mg) obtained in Example 152- (3) in tetrahydrofuran (4 mL), an aqueous solution of 1 N sodium hydroxide (2 mL) was added. The mixed solution was stirred at room temperature for three hours. Water and a 1N hydrochloric acid aqueous solution were added in an ice bath, followed by extraction with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent to give the acid 1- (4- {[2- (4-chlorophenyl) ethyl] sulfamoyl) .}. benzyl) isoquinoline-4-carboxylic acid (164 mg) as a pale yellow solid.
RM? (600 MHz, DMS0-d6) d ppm 2.58 - 2.65 (m, 2 H), 2.87 - 2.96 (m, 2 H), 4.82 (s, 2 H), 7.05 - 9.03 (m, 14 H), 13.45, (br. s., 1 H) (5) To a solution of the compound (164 mg) obtained in Example 152- (4) in chloroform (4 ml), oxalyl chloride (0.058 ml) and?,? - dimethylformamide (0.004 ml) were added in a bath of ice, and the mixed solution was stirred at room temperature for one hour, and evaporated under reduced pressure to remove the solvent. To the resulting crude product, tetrahydrofuran (2 ml) and acetonitrile (2 ml) were added, and dropwise (trimethylsilyl) diazomethane (0.341 ml, solution 2) was added in an ice bath. The mixed solution was stirred in an ice bath for one hour. The solution was evaporated under reduced pressure to remove the solvent. To the resulting crude product, water (2 ml), 1,4-dioxane (2 ml) and silver acetate (17 mg), and the solution was stirred at 60 ° C for 30 minutes. The reaction solution was filtered through celite, and water was added to the filtrate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (acidic OH-type silica gel, methanol / chloroform = 0 to 15%), and diethyl ether was added thereto, and the purified product was stirred at room temperature for 15 hours. The resulting solid was filtered and dried to give the title compound (50 mg) as a pale yellow solid.
The structural formulas and NMR values of Examples 148 to 152 are shown in Table 5.
[Ka 27] Table 5 Example 153 Acid [1- (4- { [2- (4-chlorophenyl) ethyl] carbamoyl.} Benzyl) isoquinolin-4-yl] acetic acid (1) To a solution of 4- (bromomethyl) benzoic acid tert-butyl ester (22.1 g) in toluene (440 ml), tri-n-butylphosphine (30.5 ml) was added, and the mixed solution was stirred at 60 ° C for 70 minutes. The reaction solution was removed by evaporation under reduced pressure, and to the resulting crude product, n-hexane was added and stirred. The resulting solid was filtered to give [4- (tert-butoxycarbonyl) benzyl] (tributyl) phosphonium bromide (36.0 g) as a colorless solid.
RM XH (600 MHz, CHLOROFORM-d) d ppm 0.93 - 0.98 (m, 9 H), 1.44 - 1.52 (m, 12 H), 1.60 (s, 9 H), 2.37 - 2.46 (m, 6 H), 4.34 - 4.40 (m, 2 H), 7.50 - 8.02 (m, 4 H) (2) To a solution of the compound (33.8 g) obtained in Example 153- (1) and the methyl ester of 1-chloro-isoquinoline-4-carboxylic acid (11.3 g) in tetrahydrofuran (235 ml), bis was added. Sodium (trimethylsilyl) amide (64 ml, 1.9 M solution) dropwise at -30 ° C, and the resulting solution was stirred at room temperature for 45 minutes. In addition, the resulting solution was stirred at 50 ° C for 75 minutes, and then a solution of sodium carbonate (10.2 g) in water (120 ml) was added, the resulting solution was stirred at 60 ° C for two hours. An aqueous solution of 1N hydrochloric acid was added to adjust the solution to pH5, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH-type silica gel, ethyl acetate / n-hexane = 10 to 30%) to give 1- [4- (tert-butoxycarbonyl) benzyl] isoquinoline-4- Methyl carboxylate (12.0 g) as an orange oily substance.
XH NMR (600 MHz, CHLOROFORM-d) d ppm 1.55 (s, 9 H), 4.02 (s, 3 H), 4.76 (s, 2 H), 7.27 - 8.98 (m, 8 H), 9.14 (s, 1 HOUR) (3) To a solution of the compound (11.8 g) obtained in Example 153- (2) in tetrahydrofuran (150 ml), an aqueous solution of 1 N sodium hydroxide (150 ml) was added, and the mixed solution was stirred at 50 ° C for 2.5 hours. The resulting solution was returned to room temperature, an aqueous solution of 1N hydrochloric acid was added to adjust the solution to pH 5, followed by extraction with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove the solvent to give 1- [4- (tert-butoxycarbonyl) benzyl] isoquinoline-4-carboxylic acid ( 11.1 g) as a pale orange solid.
NMR ¾ (600 MHz, DMSO-d6) d ppm 1.50 (s, 9 H), 4.76 (s, 2 H), 7.38 - 8.99 (m, 9 H) (4) To a solution of the compound (11.1 g) obtained in Example 153- (3) in chloroform (265 ml), oxalyl chloride (5.1 ml) and N, N-dimethylformamide (0.1 ml) were added in a bath of ice, and the mixed solution was stirred in an ice bath for 70 minutes, and evaporated under reduced pressure to remove the solvent. To the resulting crude product, tetrahydrofuran (133 ml) and acetonitrile (133 ml) were added, and dropwise (trimethylsilyl) diazomethane (29.5 ml, 2 M solution) was added in an ice bath. The mixed solution was stirred in an ice bath for three hours. The solvent was removed by evaporation under reduced pressure, and to the crude product Then, water (133 ml) and 1,4-dioxane (133 ml) and silver acetate (2.95 g) were added, and the mixed solution was stirred at 60 ° C for 45 minutes. The solution was returned to room temperature, and water was added to the solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. To the resulting crude product, methanol (265 ml) was added, and dropwise (trimethylsilyl) diazomethane (44.2 ml, 2 M solution) was added dropwise at room temperature, and the solution was stirred for 20 minutes. The solvent was removed by evaporation under reduced pressure, and the resulting crude product was purified by column chromatography (neutral OH-type silica gel, ethyl acetate / n-hexane = 10 to 40%) to give 4-. { [4- (2-methoxy-2-oxoethyl) isoquinolin-1-yl] methyl} tert-butyl benzoate (4.07 g) as a brown oily substance.
R XH (600 MHz, CL0R0F0RM0-d) d ppm 1.55 (s, 9 H), 3.69 (s, 3 H), 4.01 (s, 2 H), 4.70 (s, 2 H), 7.29 - 8.13 (m, 8 H), 8.41 (s, 1 H) (5) To a solution of the compound (4.07 g) obtained in Example 153- (4) in chloroform (40 ml), trifluoroacetic acid (20 ml) was added in an ice bath, and the mixed solution was stirred in a Ice bath for 30 minutes. In addition, the solution was stirred at room temperature by 3.5 hours, and then an aqueous solution of 1 N sodium hydroxide was added to the solution in an ice bath to adjust the solution to pH 5, followed by extraction with ethyl acetate. The organic layer was washed with a saturated saline solution, then dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove the solvent to give the acid 4-. { [4- (2-methoxy-2-oxoethyl) isoquinolin-1-yl] methyl} benzoic (3.42 g) as a pale brown solid.
X H NMR (600 MHz, DMSO-d 6) d ppm 3.62 (s, 3 H), 4.13 (s, 2 H), 4.71 (s, 2 H), 7.39- 8.36 (m, 8 H), 8.37 (s, 1 H), 12.79 (br. S., 1 H) (6) To a solution of the compound (2.69 g) obtained in Example 153- (5) in chloroform (40 ml), oxalyl chloride (1.07 ml) and N, N-dimethylformamide (3 drops) were added in a bath of ice, and the mixed solution was stirred for one hour. The reaction solution was removed by evaporation under reduced pressure. Chloroform (40 ml) was added to the resulting crude product, and 2- (4-chlorophenyl) ethylamine (1.68 ml) and pyridine (0.973 ml) were added in an ice bath, and the resulting solution was stirred for one hour. The reaction solution was washed with a saturated solution of ammonium chloride, and the organic layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (NH type silica gel, ethyl acetate ethyl / n-hexane = 10 to 100%) to give methyl [1- (4- ({[[(4-chlorophenyl) ethyl] carbamoyDbenzyl) isoquinolin-4-yl] acetate (1.31 g) as a Pale yellow solid.
RM XH (600 MHz, CL0R0F0RM0-d) d ppm 2.87 (t, J = 6.9 Hz, 2 H), 3.61 - 3.67 (m, 2 H), 3.70 (s, 3 H), 4.01 (s, 2 H) , 4.68 (s, 2 H), 6.04 (t, J = 5.3 Hz, 1 H), 7.11 - 8.13 (m, 12 H), 8.40 (s, 1 H) (7) To a solution of the compound (1.31 g) obtained in Example 153- (6) in tetrahydrofuran (55 ml), an aqueous solution of 1 N sodium hydroxide (14 ml) was added in an ice bath, and The mixed solution was stirred at room temperature for 2.5 hours. An aqueous solution of 1 N hydrochloric acid in an ice bath was added to the solution to adjust the solution to pH 5, followed by extraction with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (acid OH-type silica gel, methanol / chloroform = 0 to 15%). To the obtained solid diethyl ether was added, and the mixture was stirred at room temperature for 17 hours to be filtered to give a pale yellow solid (1.05 g). The solid obtained was dissolved in ethanol (250 ml) at 40 ° C, and water (2500 ml) was added thereto dropwise, and the resulting solution was stirred at room temperature for 17 hours. The solid precipitate was filtered and dried to give the title compound (944 mg) as a pale yellow solid.
The compounds of Examples 154 to 160 were obtained by carrying out the same procedures as in Example 153. The structural formulas and NMR values of Examples 153 to 160 are shown in Table 6.
[Ka 28] Table 6 Example 161 Acid (l- { 4- [(2-phenylethyl) carbamoyl] benzyl]. Isoquinolin-4-yl) acetic acid (1) To a suspension of the compound (100 mg) obtained in Example 153- (5), 2-phenylethylamine (0.045 ml) and hydrated 1-hydroxybenzotriazole (55 mg) in chloroform (3 ml), was added hydrochloride. ethyl-3- (dimethylaminopropyl) -carbodiimide (69 mg), and the mixture was stirred at room temperature for three hours. The reaction solution was washed with water, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (silica gel type H, ethyl acetate / n-hexane = 60 to 100%) to give (l-. {4- [(2-phenyl ethyl) carbamoyl]] methyl benzyl.} isoquinolin-4-yl) acetate (90 mg) as a pale brown solid.
NMR XH (600 MHz, CL0R0F0RM0-d) d ppm 2.90 (f, J = 6.9 Hz, 2 H), 3.66 - 3.72 (m, 5 H), 4.01 (s, 2 H), 4.68 (s, 2 H) , 5.98 - 6.07 (m, 1 H), 7.18 - 8.14 (m, 13 H), 8.40 (s, 1 H) (2) The same procedure as that used in Example 149- (4) was carried out using the compound (90 mg) obtained in Example 161- (1) to give the title compound (73 mg) as a solid pale yellow.
The compounds of Examples 162 to 251 were obtained by carrying out the same procedures as in Example 161. The structural formulas and NMR values of Examples 161 to 251 are shown in Tables 7-1 to 7-9.
[Ka 29] Table 7-1 Table 7-2 Table 7-3 Table 7-4 Table 7-5 Table 7-6 Table 7-7 Table 7-8 Table 7-9 Example 252 Acid (1- (2- [(4-chlorobenzyl) oxy] benzyl] isoquinolin-4-yl) acetic acid (1) The same procedure as that used in the Example 153- (1) was carried out using 2-methoxybenzyl chloride (3.81 g) to give tributyl (2-methoxybenzyl) phosphonium chloride (8.13 g) as a colorless solid.
XH NMR (600 MHz, CHLOROFORM-d) 'd ppm 0.89 - 0.97 (m, 9 H), 1.38 - 1.51 (m, 12 H), 2.37 - 2.47 (m, 6 H), 3.85 (s, 3 H), 4.10 - 4.16 (m, 2 H), 6.87 - 7.75 (m, 4 H) (2) The same procedure as that used in Example 153- (2) was carried out using the compound (2.27 g) obtained in Example 252- (1) to give the l- (2-methoxybenzyl) isoquinoline-4 Methylcarboxylate (436 mg) as a pale orange solid.
XH NMR (600 MHz, CHLOROFORM-d) d ppm 3.89 (s, 3 H), 4.01 (s, 3 H), 4.71 (s, 2 H), 6.75 - 8.99 (m, 8 H), 9.13 (s, 1 | H) (3) The same procedure as the one used in the Example 153- (3) was carried out using the compound (436 mg) obtained in Example 252- (2) to give l- (2-methoxybenzyl) isoquinoline-4-carboxylic acid (335 mg) as a yellow solid pale.
XH NMR (600 MHz, DMS0-d6) d ppm 3.82 (s, 3 H), 4.63 (s, 2 H), 6.76 - 8.93 (m, 8 H), 8.96 (s, 1 H), 13.38 (br. s., 1 H) (4) The same procedure as that used in Example 153- (4) was carried out using the compound (335 mg) obtained in Example 252- (3) to give [1- (2-methoxybenzyl) isoquinoline- 4-yl] methyl acetate (108 mg) as a brown oily substance.
NMR ½ (600 MHz, CHLOROFORM-d) d ppm 3.69 (s, 3 H), 3.91 (s, 3 H), 4.01 (s, 2 H), 4.65 (s, 2 H), 6.75 - 8.24 (m, 8 H), 8.40 (S, 1 H) (5) The same procedure as that used in Example 149- (2) was carried out using the compound (70 mg) obtained in Example 252- (4) to give [1- (2-hydroxybenzyl) isoquinoline- 4-yl] methyl acetate (39 mg) as a yellow solid.
NMR XH (600 MHz, CHLOROFORM-d) d ppm 3.68 (s, 3 H), 3.98 (s, 2 H), 4.60 (s, 2 H), 6.79 - 8.52 (m, 9 H), 11.41 (br. s., 1 H) (6) The same procedure as that used in Example 134- (5) was carried out using the compound (39 mg) obtained in Example 252- (5) and 4-chlorobenzyl bromide (42 mg) to give the . { 1- [2- (4-chlorobenzyloxy) benzyl] isoquinolin-4-yl} Methyl acetate (57 mg) as a yellow oily substance.
XH NMR (600 MHz, CHLOROFORM-d) d ppm 3.69 (S, 3 H), 4. 00 (s, 2 H), 4.68 (s, 2 H), 5.08 (s, 2 H), 6.81 - 8.20 (m, 12 H), 8.38 (s, 1 H) (7) The same procedure as that used in Example 149- (4) was carried out using the compound (57 mg) obtained in Example 252- (6) to give the title compound (25 mg) as a solid pale yellow.
Example 253 Acid [1- (4- { [2- (4-chlorophenyl) ethyl] carbamoiDbenzyl) -6-fluoro-isoquinolin-4-yl] acetic acid (1) To methyl 6-fluoro-l-oxo-1,2-dihydroisoquinoline-4-carboxylate (756 mg), phosphoryl chloride was added (5 ml), and the mixture was stirred at 100 ° C for one hour. The resulting solution was returned to room temperature, and evaporated under reduced pressure to remove the solvent. To the resulting crude product, saturated sodium bicarbonate-water was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent to give methyl 1-chloro-6-fluoroisoquinoline-4-carboxylate (792 mg) as a solid. coffee.
NMR XH (600 Hz, CHLOROFORM-d) d ppm _ 4.03 (s, 3 H), 7.48 - 8.77 (m, 3 H), 8.97 (s, 1 H) (2) To a solution of 4- (bromomethyl) benzoic acid (5.00 g) in chloroform (40 ml), oxalyl chloride (4 ml) and?,? - dimethylformamide '(2 drops) were added in an ice bath. , and the mixed solution was stirred at room temperature for three hours. The reaction solution was removed by evaporation under reduced pressure, and to the resulting crude product, toluene (70 ml) and n-hexane (70 ml) were added. The resulting solution was stirred at room temperature while 2- (4-chlorophenyl) ethylamine (3.02 g) and pyridine (1.6 ml) were added dropwise. The resulting solution was stirred at room temperature for 65 hours, and then an aqueous solution of 1 N hydrochloric acid was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH-type silica gel, ethyl acetate / n-hexane = 10 to 80%) to give 4- (bromomethyl) -N- [2- (4-chlorophenyl) ethyl] benzamide (4.36 g) as a colorless solid.
NMR ¾ (600 MHz, DMSO-d6.) D ppm 2.84 (t, J = 7.1 Hz, 2 H), 3.44 - 3.51 (m, 2 H), 4.73 (s, 1 H), 4.80 (s, 1 H) ), 7.22 -7.83 (m, 8 H), 8.51 - 8.59 (m, 1 H) (3) The same procedure as that used in Example 153- (1) was carried out using the compound (4.35 g) obtained in Example 253- (2) to give tributyl bromide (4- { 2- (4-chlorophenyl) ethyl] carbamoyl.} Benzyl) phosphonium (6.01 g) as a colorless solid.
NMR XH (600 MHz, CHLOROFORM-d) d ppm 0.86 - 0.96 (m, 9 H), 1.40 - 1.50 (m, 12. H), 2.28 - 2.38 (m, 6 H), 3.00 (t, J = 7.6 Hz, 2 H), 3.67 - 3.74 (m, 2 H), 4.36 - 4.42 (m, 2 H), 7.21 - 7.90 (m, 9 H) (4) To a solution of the compound (787 mg) obtained in Example 253- (1) and the compound (2.19 g) obtained in Example 253- (3) in tetrahydrofuran (15 ml), sodium bis (trimethylsilyl) mide (5.5 ml, 1.9 solution) was added dropwise to -30 ° C, and the solution was stirred at room temperature for one hour. In addition, the solution was stirred at 50 ° C for two hours, and then a solution of sodium carbonate (695 mg) in water (7 ml) was added. The solution was stirred at 60 ° C for five hours. The solution was stirred at room temperature for 16 hours, and then an aqueous 1 N hydrochloric acid solution was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH-type silica gel, methanol / chloroform = 10%) to give the acid 1- (4- {[2- (4-chlorophenyl) ethyl] carbamoyl}. benzyl) -6-fluoroisoquinoline-4-carboxylic acid (180 mg) as a colorless solid.
RN 1H (600 MHz, DMSO-d6) d ppm 2.80 (t, J = 7.3 Hz, 2 H), 3.40 - 3.47 (m, "2 H), 4.77 (s, 2 H), 7.21 - 8.71 (m, 12 H), 9.07 (s, 1 H), 13.55 (br. S., 1 H) (5) The same procedure as that used in Example 152- (5) was carried out using the compound (173 mg) obtained in Example 253- (4) to give the title compound (5 mg) as a solid colorless.
Example 254 2- [1- (4- { [2- (4-chlorophenyl) ethyl] carbamoyl} benzyl) isoquinolin-4-yl] propanoic acid (1) To a solution of the compound (500 mg) obtained in Example 153- (4) in tetrahydrofuran (5 ml), tert-butoxy potassium (150 mg) was added at -30 ° C, and the mixed solution was stirred for 5 minutes, and then methyl iodide (0.159 ml) was added. The mixed solution was stirred for 1.5 hours. In addition, methyl iodide (0.159 ml) was added thereto at -30 ° C, and the solution was stirred for 1.5 hours, and a saturated aqueous solution of ammonium chloride was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH-type silica gel, ethyl acetate / n-hexane = 10 to 20%) to give 4-. { [4- (1-methoxy-1-oxopropan-2-yl) isoquinolin-1-yl] methyl} tert-butyl benzoate (319 mg) as a yellow oily substance.
XH NMR (600 MHz, CHLOROFORM-d) d ppm 1.55 (s, 9 H), 1. 70 (d, J = 7.0 Hz, 3 H), 3.67 (s, 3 H), 4.36 (q, J = 7.0 Hz, 1 H), 4.70 (s, 2 H), 7.30 - 8.14 (m, 8 H) ), 8.45 (s, 1 H) (2) The same procedure as that used in Example 153- (5) was carried out using the compound (319 mg) obtained in Example 254- (1) to give the acid 4-. { [4- (l- methoxy-1-oxopropan-2-yl) isoquinolin-1-yl] methyl} benzoic acid (254 mg) as a pale yellow solid.
RMN 1 ?? (600 Hz, DMSO-d6) d ppm 1.58 (d, J = 6.9 Hz, 3 H), 3.59 (s, 3 H), 4.56 (q, J = 6.9 Hz, 1 H), 4.73 (s, 2 H) ), 7.42 - 8.41 (m, 9 H) (3) The same procedure as that used in Example 161- (1) was carried out using the compound (254 mg) obtained in Example 254- (2) to give 2- [1- (4-. { Methyl [2- (4-chlorophenyl) ethyl] carbamoyl] benzyl) isoquinolin-4-yl] propanoate (234 mg) as a pale yellow amorphous substance.
NMR ½ (600 MHz, CHLOROFORM-d) d ppm 1.70 (d, J = 7.2 Hz, 3 H), 2.87 (t, J = 6.9 Hz, 2 H), 10 3.63 - 3.66 (m, 2 H), 3.67 (s, 3 H), 4.36 (q, J = 7.2 Hz, 1 H), 4.68 (s, 2 H), 6.03 (br. s., 1 H), 7.12 - 8.14 (m, 12 H), 8.45 (s, 1 H) (4) The same procedure as that used in Example 149- (4) was carried out using the compound (110 mg) obtained in Example 254- (3) to give the title compound (58 mg) as a solid colorless.
Emplo 255 Acid 2-. { l- [(4- {[2- (4-chlorophenyl) ethyl] carbamoyl} phenyl) Carbo-nil] isoquinolin-4-yl} -2-methylpropanoic (1) To a solution of the compound (181 mg) obtained in Example 135- (3) in N, N-dimethylformamide (3.6 ml), sodium hydride (38 mg) was added in an ice bath. " The solution mixed was stirred for 10 minutes, and methyl iodide (0.058 ml) was added thereto, and the mixed solution was stirred for 1.5 hours. A saturated aqueous solution of ammonium chloride was added, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH-type silica gel, ethyl acetate / n-hexane = 10 to 30%) to give 4-. { [4- (1-methoxy-2-methyl-l-oxopropan-2-yl) isoquinolin-1-yl] carbonyl} tert-butyl benzoate (139 mg) as a colorless amorphous substance.
NMR ¾ (600 MHz, CHLOROFORM-d) d ppm 1.61 (s, 9 H), 1.84 (s, 6 H), 3.63 (s, 3 H), 7.59 - 8.31 (m, 8 H), 8.65 (s, 1 HOUR) (2) The same procedure as that used in Example 153- (5) was carried out using the compound (139 mg) obtained in Example 255- (1) to give the acid 4-. { [4- (1-methoxy-2-methyl-l-oxopropan-2-yl) isoquinolin-1-yl] carbonyl} benzoic acid (128 mg) as a colorless amorphous substance.
X H NMR (600 MHz, DMSO-d 6) d ppm 1.75 (s, 6 H), 3.55 (s, 3 H), 7.68 - 8.17 (m, 8 H), 8.66 (s, 1 H) (3) The same procedure as that used in Example 161- (1) was carried out using the compound (128 mg) obtained in Example 255- (2) to give 2-. { l- [(4- {[2- (4-chlorophenyl) ethyl] carbamoyl} phenyl) carbonyl] isoquinolin-4-yl} Methyl -2-methylpropanoate (73 mg) as a colorless amorphous substance.
NMR ¾ (600 MHz, CL0R0F0RM0-d) d ppm 1.84 (s, 6 H), 2.91 - 2.95 (m, 2 H), 3.63 (s, 3 H), 3.69 - 3.75 (m, 2 H), 6.10 - 6.15 (m, 1 H), 7.15 - 8.33 (m, 12 H), 8.64 (s, 1 H) (4) To a solution of the compound (70 mg) obtained in Example 255- (3) in 1,4-dioxane (1.4 ml), an aqueous solution of 1 N lithium hydroxide (1.4 ml) was added, and the Mixed solution was stirred at 100 ° C for one hour. The solution was adjusted to pH 4 by adding aqueous 1 N hydrochloric acid solution, and then extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (acidic OH-type silica gel, ethyl acetate / n-hexane = 30 to 60%), diethyl ether was added thereto, and the resulting solution was stirred for 15 hours. The produced solid was filtered to give the title compound (21 mg) as a pale yellow solid.
Example 256 4- . { [4- (2-amino-2-oxoethyl) isoquinolin-1-yl] methyl} -N- [2 - (4-chlorophenyl) ethyl] benzamide To a suspension of the compound (400 mg) obtained in Example 153- (7) in tetrahydrofuran (9 ml), 1,1'-carbonyl diimidazole (283 mg) was added. The mixed solution was stirred at room temperature for two hours. Then, 28% aqueous ammonia (0.45 ml) was added thereto, and the resulting solution was stirred at room temperature for one hour. The precipitate was filtered and dried to give the title compound (384 mg) as a colorless solid.
Example 257 N- [2- (4-chlorophenyl) ethyl] -4-. { [4- (lH-tetrazol-5-ylmethyl) is-quinolin-1-yl] methyl} benzamide (1) To the compound (362 mg) obtained in Example 256- (1), phosphoryl chloride (0.088 ml) was added, and the mixed solution was stirred at room temperature for one hour. To the reaction solution, ice water was added, followed by extraction with chloroform. Then, the organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH-type silica gel, methanol / chloroform = 2 to 10%) to give N- [2- (4-chlorophenyl) ethyl] -4-. { [4- (cyanomethyl) isoquinolin-1- il] methyl} Benzamide (256 mg) as a pale yellow solid.
NMR ½ (600 MHz, DMSO-d6) d ppm 2.80 (t, J = 7.3 Hz, 2 H), 3.40 - 3.47 (m, 2 H), 4.45 (s, 2 H), 4.70 (s, 2 H) , 7.20 -8.44 (m, 13 H), 8.49 (s, 1 H) (2) To a suspension of the compound (20 mg) obtained in Example 257- (1) in toluene (0.45 ml), sodium azide (9 mg) and triethylamine hydrochloride (19 mg) were added, and the mixture was subjected to reflux for 72 hours. Methanol / chloroform (10%) was added thereto. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH-type silica gel, methanol / chloroform = 10 to 20%). To the resulting solid, methanol / chloroform (10%) was added, and the mixture was washed with 0.5 N hydrochloric acid aqueous solution, and then washed with water. The organic layer was dried over anhydrous magnesium sulfate and then evaporated under reduced pressure to remove the solvent to give the title compound (3.1 mg) as a colorless solid.
Example 258 N- [2- (4-chlorophenyl) ethyl] -4- (. {4- [2- (hydroxyamino) -2-oxoethyl] iso-quinolin-1-yl} methyl) benzamide (1) To a solution of the compound (41 mg) obtained in Example 153- (7), 0- (tetrahydro-2H-pyran-2-yl) hydroxylamine (12 mg) and hydrated 1-hydroxybenzotriazole (15 mg) in?,? -dimethylformamide (2 ml), l-ethyl-3- (dimethylaminopropyl) -carbodiimide hydrochloride (19 mg) was added, and the mixed solution was stirred at room temperature for one hour. Ethyl acetate was added, and the reaction solution was washed with water and then washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH-type silica gel, methanol / chloroform = 0 to 20%) to give N- [2- (4-chlorophenyl) ethyl] -4- [(4- {2 - ??? - 2- [(Tetrahydro-2H-pyran-2-yloxy) amino] ethyl} - isoquinolin-1-yl) methyl] benzamide (49 mg) as a pale yellow solid.
RM XH (600 MHz, CHLOROFORM-d) d ppm 1.20 - 1.85 (m, 6 H), 2.83 - 2.91 (m, 4 H), 3.59 - 3.98 (m, 5 H), 4.67 (s, 2 H), 4.84 - 4.95 (m, 1 H), 5.98 - 6.07 (m, 1 H), 7.10 - 8.29 (m, 12 H), 8.40 (s, 1 H) (2) To a solution of the compound (49 mg) obtained in Example 258- (1) in methanol (2 ml), 4 N hydrochloric acid-ethyl acetate (0.223 ml) was added in an ice bath, and the Mixed solution was stirred at room temperature for three hours. Chloroform was added thereto, and the reaction solution was washed with water and then washed with a saturated saline solution. The organic layer was dried over magnesium sulfate anhydrous, and then evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH-type silica gel, methanol / chloroform = 2 to 20%) to give the title compound (17 mg) as a pale yellow solid.
Example 259 Acid { l - [(4- {[2- (4-chlorophenyl) ethyl] carbamoyl} phenyl) carbonyl] -6,7-dimethoxyisoquinolin-4-yl} acetic (1) To a solution of 4- (2-methoxy-2-oxoethyl) benzoic acid (1.00 g) in acetonitrile (50 ml), N, -diisopropyl ethyl amine (2.63 ml) was added., 0- (7-azabenzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate (2.94 g) and 2- (4-chlorophenyl) ethylamine (790 ml), and the mixed solution was stirred at room temperature. room temperature for 16 hours. The solvent was removed by evaporation under reduced pressure, and the resulting crude product was purified by column chromatography (neutral OH type silica gel, ethyl acetate / n-hexane 30 to 50%) to give the (4- { [2- (4-chlorophenyl) ethyl] carbamoyl.] Phenyl) -acetic acid methyl ester (2.02 g).
NMR XH (600 MHz, CL0R0F0RM0-d) d ppm 2.88-2.93 (m, 2 H), 3.65 - 3.72 (m, 7 H), 6.08 - 6.19 (m, 1 H), 7.14 - 7.35 (m, 7 H) ), 7.63 - 7.67 (m, 1 H) (2) The same procedure as that used in Example 153- (3) was carried out using the compound (2.02 g) obtained in Example 259- (1) to give the acid (4- {[2- (4-chlorophenyl) ethyl] carbamoyl} phenyl) acetic acid (1.78 g). 1 H NMR (600 MHz, CHLOROFOR O-d) d ppm 2.88-2.93 (m, 2 H), 3.67 - 3.72 (m, 4 H), 6.09 (br. S., 1 H), 7.15 - 7.67 (m, 8 H) (3) To a solution of the compound (250 mg) obtained in Example 259- (2) in N, N-dimethylformamide (8 ml), N, N-diisopropyl ethyl amine (0.401 ml), hexafluorophosphate 0- (7). -azabenzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium (449 mg) and ethyl 4-amino-3- (3,4-dimethoxyphenyl) butanoate (231 mg) were added, and the mixed solution was stirred at room temperature for 15 hours. Ethyl acetate was added thereto, and the reaction solution was washed with water and then washed with a saturated saline solution. The solvent was removed by evaporation under reduced pressure, and the resulting crude product was purified by column chromatography (neutral OH-type silica gel, ethyl acetate / n-hexane = 30 to 75%) to give 4-. { [(4- {[2- (4-chloro-phenyl) ethyl] carbamoyl} phenyl) acetyl] amino} Ethyl -3- (3,4-dimethoxyphenyl) butanoate (130 mg).
NMR E (600 MHz, CHLOROFORM-d) d ppm 1.11 - 1.20 (m, 3 H), 2.49 - 4.10 (m, 19 H), 5.18 10 - 5.24 (m, 1 H), 6.30 -6.36 (m, 1 H), 6.51 - 7.57 (m, 11 H) (4) To a solution of the compound (130 mg) obtained in Example 259- (3) in chloroform (2.3 ml), 2- was added chloropyridine (0.026 ml) and cooled to -60 ° C, and then trifluoromethanesulfonic anhydride (0.042 ml) was added. The mixed solution was stirred for 15 minutes. The resulting solution was stirred for 5 minutes in an ice bath, and further stirred at room temperature for one hour. Saturated sodium bicarbonate-water was added, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then evaporated under reduced pressure to remove the solvent. To the resulting crude product, sulfur (9 mg) was added, and the mixed solution was stirred at 165 ° C for 15 minutes. Ethanol was added and the insolubles were removed by filtration, and the solvent in the filtrate was removed by evaporation under reduced pressure. The resulting crude product was purified by column chromatography (neutral OH-type silica gel, ethyl acetate / n-hexane = 33 to 75%) to give the. { 1- [(4- {[2- (4-chlorophenyl) ethyl] carbamoyl} phenyl) carbonyl] -6,7-dimethoxyisoquinolin-4-yl} ethyl acetate (30 mg).
RM 1H (600 MHz, CHLOROFORM-d) d ppm 1.23-1.28 (m, 3 H), 2.91-2.95 (m, 2 H), 3.69 - 3.74 (m, 2 H), 3.99 (s, 3 H), 4.03 (s, 2 H), 4.07 (s, 3 H), 4.16 - 4.21 (m, 2 H), 6.13 -6.17 (m, 1 H), 7.15 - 8.02 (m, 10 H), 8.38 (s, 1 HOUR) (5) The same procedure as that used in Example 149- (4) was carried out using the compound (27 mg) obtained in Example 259- (4) to give the title compound (7 mg) as a solid pale yellow.
Example 260 Acid { l - [(4- {[2- (4-chlorophenyl) ethyl] carbamoyl} phenyl) carbonyl] -6-methoxyisoquinolin-4-yl} acetic (1) To a solution of ethyl 3-cyano-3- (3-methoxypheniDpropanoate (11.9 g) in ethanol (41 ml), 12N hydrochloric acid (3.8 ml) and 20% palladium hydroxide on carbon ( 2.10 g), and the mixed solution was stirred under an atmosphere of hydrogen at room temperature for 15 hours.The solvent was removed by evaporation under reduced pressure, and the resulting crude product was purified by column chromatography (neutral OH-type silica gel). , methanol / chloroform = 2 to 9%) to give ethyl 4-amino-3- (3-methoxyphenyl) butanoate (3.80 g).
RM NMR (600 MHz, CHLOROFORM-d) d ppm 1.11 - 1.16 (m, 3 H), 2.65 - 2.72 (m, 1 H), 2.79 - 2.86 (m, 1 H), 3.06 - 3.12 (m, 1 H ), 3.24 - 3.30 (m, 1 H), 3.46 - 3.53 (m, 1 H), 3.76 - 3.79 (m, 3 H), 4.00 - 4.07 (m, 2 H), 6.76 - 7.26 (m, 4 H) ) (2) The same procedure as that used in Example 153- (6) was carried out using the compound (280 mg) obtained in Example 260- (1) and the compound (250 mg) obtained in Example 259- (2) to give the 4-. { [(4- { [2- (4-chlorophenyl) ethyl] carbamoyl.] Phenyl) acetyl] amino} Ethyl -3- (3-methoxyphenyl) butanoate (210 mg).
XH NMR (.600 MHz, CHLOROFORM-d) d ppm 1.12 - 1.18 (m, 3 H), 2.52 - 2.61 (m, 2 H), 2.90 - 2.95 (m, 2 H), 3.18 - 3.32 (m, 2 H), 3.48 (s, 2 H), 3.58 - 3.64 (m, 1 H), 3.68 - 3.73 (m, 2 H), 3.74 (s, 3 H), 4.01 - 4.07 (m, 2 H), 5.25 - 5.30 (m, 1 H), 6.14 - 6.19 (m, 1 H), 6.57 - 7.60 (m, 12 H) ) (3) The same procedure as that used in Example 259- (4) was carried out using the compound (201 mg) obtained in Example 260- (2) to give the. { 1- [(4- {[2- (4-chlorophenyl) ethyl] carbamoyl} phenyl) carbonyl] -6-methoxyisoquinolin-4-yl} ethyl acetate (40 mg). 1 H NMR (600 MHz, CHLOROFORM-d) d ppm 1.26 (t, J = 7.3 Hz, 3 H), 2.90-2.95 (m, 2 H), 3.69 - 3.73 (m (2 H), 3.99 (s, 3 H), 4.04 (s, 2 H), 4.20 (q, J = 7.3 Hz, 2 H), 6.12 - 6.16 (m, 1 H), 7.15 - 8.24 (m, 11 H), 8.44 (s, 1 H) (4) The same procedure as that used in Example 149- (4) was carried out using the compound (37 mg) obtained in Example 260- (3) to give the title compound (20 mg) as a solid pale yellow.
Example 261 Acid [1- (4- { [2- (4-chlorophenyl) ethyl] carbamoyl.}. Phenoxy) isoquinolin-4-yl] acetic acid (1) A suspension of N- [2- (4-chlorophenyl) ethyl] -4-hydroxybenzamide (605 mg) and methyl ester of 1-chloro-isoquinoline-4-carboxylic acid (443 mg) and potassium carbonate ( 332 mg) in DMF (4 ml) was stirred at 60 ° C for two hours. Ethyl acetate was added thereto, and the reaction solution was washed with water, and then washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (NH type silica gel, chloroform / n-hexane = 50 to 80%) to give l- (4- {[2- (4-chlorophenyl) ethyl]] carbamoyl.}. phenoxy) isoquinoline-4-carboxylic acid methyl ester (782 mg) as a colorless solid.
R XH (600 MHz, CHLOROFORM-d) d ppm 2.93 (t, J = 7.1 Hz, 2 H), 3.70 - 3.76 (m, 2 H), 3.98 (s, 3 H), 6.10 (t, J = 5.5 Hz, 1 H), 7.15 - 8.52 (m, 11 H), 8.72 (s, 1 H), 9.01 (d, J = 8.3 Hz, 1 H) (2) The same procedure as that used in Example 152- (4) was carried out using the compound (782 mg) obtained in Example 261- (1) to give the acid l- (4- { 2- (4-chlorophenyl) ethyl] carbamoyl.} Phenoxy) isoquinoline-4-carboxylic acid (781 mg) as a colorless solid.
NMR * H (600 MHz, DMSO-de) d ppm 2.87 (t, J = 7.1 Hz, 2 H), 3.48 - 3.54 (m, 2 H), 7.26 - 9.01 (m, 14 H) (3) The same procedure as the one used in the Example 152- (5) was carried out using the compound (350 mg) obtained in Example 261- (2) to give the title compound (5 mg) as a colorless solid.
The structural formulas and NMR values of Examples 252 to 261 are shown in Tables 8-1 to 8-2.
Table 8-1 Table 8-2 Test Example. CRTH2 link test The CRTH2 binding inhibitory activity of the compound of the present invention was considered when using a binding test between the human CRTH2 expression cell KB8 (BML, INC.) And 3H-labeled prostaglandin D2 (hereinafter herein) , abbreviated as 3H-PGD2, manufactured by GE Healthcare).
KB8 was suspended in a reaction pH buffer (Hank's balanced salt solution (Invitrogen) containing 10 mM HEPES (Invitrogen)), which was dispensed into a 96-well plate (Coaster) in such a way that 2xl05 cells / cavity they are placed. In addition, the compound of the present invention and 3H-PGD2 (final concentration: 5 nM) were Aggregates, stirred and incubated at 4 ° C.
One hour later, cells were collected on the plate of GF / C Filter (PerkinElmer) that had been pre-coated with 0.5% polyethyleneimine solution (SIG A) when using a cell harvester (Packard BioScience), and the radioactivity of the cells was measure when using Top count NXT (PerkinElmer) (a value measured in the present was represented by a measurement value "a"). The same procedure was carried out in the absence of the compound, and a measurement value "b" was obtained; and the same procedure was carried out in the absence of the compound and in the presence of unlabeled PGD2 (final concentration: 50 μm), a measurement value "c" was obtained.
The binding inhibition ratio of the compound was calculated by the following calculation formula: Link inhibitory ratio (%) = [1- (a-c) / (b-c)] x 100 In addition, the CRTH2 binding inhibitory activity of a compound to be tested was calculated as a value (IC 50 value) exhibiting 50% inhibitory activity with respect to the amount of binding in the absence of the compound. That is, when using binding inhibition ratios of compounds to be tested that have various concentrations, the IC50 value was calculated according to the dose-dependent inhibition curve analyzed using XLfit (IDBS) as programming elements of data analysis and the calculated value was defined as an indicator of inhibitory activity. The test results are shown in Table 9. In Table 9, A denotes an inhibitory activity showing the IC50 value of less than 50 nM; B denotes an inhibitory activity showing the IC 50 value of 50 nM or greater and less than 500 nM; C denotes an inhibitory activity showing the IC50 value of 500 nM or greater and less than 1000 nM; and D denotes an inhibitory activity showing the IC50 value of 1000 nM or greater. Specific values include, for example, Example 18 (IC50 value; 3.5 nM), Example 57 (IC50 value; 3.4 nM), Example 75 (IC50 value; 2.9 nM), Example 82 (IC50 value; 2.8 nM). and Example 143 (IC 50 value, 9.9 nM).
Table 9 Example inhibitory activity link 1 A 2 A 3 A 4 A 5 A 6 A 7 A 8 A 9 A io A 1 1 A 12 A 13 A 14 TO 15 A 16 A 17 A 18 19 s 20 A 21 A 22 A 23 A 27 A 29 A 34 A Test Example 2. CRTH2 Antagonist Test The antagonist activity of the compound of the present invention was considered when using the intracellular calcium ion concentration increase reaction induced when prostaglandin D2 was added to KB8 cells.
The tetrakis (acetoxymethyl) ester of fluo-4-? (4- (6-acetoxymethoxy-2,7-difluoro-3-oxo-9-xanthenyl) -4'-methyl-2,2'- (ethylenedioxy) dianilide-N, N, N ', N' -tetraacetic ( SIGMA, final concentration: 1 μ?) Was added to KB8 cells, and the cells were incubated at 37 ° C for 30 minutes, washed with phosphate pH buffer (Invitrogen), and then suspended in Hank's balanced salt solution. (Invitrogen)) containing a buffer solution of the reaction pH (10 mM HEPES (Invitrogen), and 1 mM calcium chloride (SIGMA) .The suspension was supplied in a 96-well plate (Nunc) such that 2xl05 cells / cavity were placed, and the compound of the present invention and PGD2 (final concentration: 100 nM) were added.The fluorescence intensity thereof was measured with the passage of time when using the FDSS6000 device (Hamamatsu Photonics), and obtained the maximum fluorescence intensity value "d." The same procedure was carried out in the absence of the compound, and the maximum fluorescence value "e" was obtained; and the same procedure was carried out in the absence of the compound and in the presence of unlabeled PGD2, and obtained the maximum fluorescence intensity value * f ".
The inhibition ratio of the increase in the concentration of the calcium ion of a compound was calculated by the following calculation formula: Inhibitory ratio (%) = [1- (d-f) / (e-f)] xlOO In addition, the CRTH2 antagonist activity of a compound to be tested was calculated as a value (IC 50 value) exhibiting 50% inhibitory activity with respect to the increase in calcium ion concentration in the absence of the compound. That is, by using inhibitory ratios of the increase in the concentration of the calcium ion of compounds to be tested having various concentrations, the IC50 value was calculated according to a dose-dependent inhibition curve analyzed when using XLfit (IDBS) as a data analysis programming element and the value was defined as an indicator of the antagonist activity. The test results are shown in Tables 10-1 and 10-2. In the Tables, A denotes an inhibitory activity showing the IC50 value of less than 50 M; B denotes an inhibitory activity showing 'the IC 50 value of 50 nM or greater and less than 500 nM; C denotes an inhibitory activity showing the IC50 value of 500 nM or greater and less than 1000 nM; and D denotes an inhibitory activity showing the IC50 value of 1000 nM or greater. Specific values include, for example, Example 122 (IC50 value; 2.3 nM), Example 153 (IC50 value; nM), Example 201 (IC50 value; 20 nM), Example 234 (IC50 value; 5.9 nM), and Example 240 (IC5o value; 6.6 nM).
Table 10-1 Table 10-2 Example: antagonist activity Example antagonist activity 158 A 193 A 159 A 194 A 160 A 195 A 161 B 196 C 162 A 197 B 163 A 198 B 164 A 199 A 165 A 200 B 166 A 201 A 167 A 202 B 168 B 203 A 169 B 204 A 170 B 205 A 171 B 206 B 172 B 207 O 173 D 208 A 174 B 209 O 175 O 210 A 176 D 21 1 B 177 D 212 B 178 B 213 B 179 A 214 D 180 A 215 B 181 B 216 B 182 B 217 A 183 A 218 A 184 B 219 B 185 D 220 D 186 C 221 A 187 A 222 A 188 B 223 B 189 D 224 B 190 B 225 A 191 B 226 A 192 A 227 D Possibility of Industrial Application A compound of the present invention has CRTH2 inhibitory activity, and can be used as preventive agents or therapeutic agents for allergic diseases such as asthma, atopic dermatitis and allergic rhinitis.

Claims (14)

1. A compound represented by the formula (I): [Ka 1] wherein R1 represents a Ci_6 alkyl group, a C2-6 alkenyl group, a C3_6 cycloalkyl group, a C3_6 cycloalkenyl group, an adamantyl group, an indanyl group, a tetrahydronaphthyl group, a tetrahydroindolyl group, a tetrahydropyranyl group, a morpholinyl group, a phenyl group, a naphthyl group, or an aromatic heterocyclic group, wherein the phenyl group, the naphthyl group, and the aromatic heterocyclic group may be substituted with 1 to 5 substituents selected from the group consisting of a group CI_G alkyl, a group C2-6 alkenyl, a C3-6 cycloalkyl group, a halogen atom, a Ci_6 alkoxy group, a hydroxy group, a Ci_6 alkylthio group, a C1-6 haloalkyl group, a Ci_6 haloalkoxy group, a Ci-6 haloalkylthio group, a cyano group, a nitro group, a guanidino group, a C1-6 alkylsulfonyl group, a carboxy group, a C2.7 alkoxycarbonyl group, a C2.7 alkanoyloxy group, a phenyl group, a benzoyl group, a phenoxy group, a pyrrolyl group, a thienyl group, a group imidazolyl, a thiadiazolyl group, a morpholino group, the formula: -NR5R6, the formula: -S02NR7R8, the formula: -NR9S02R10, the formula: -C0NR1XR12, and the formula: -NR13COR14, wherein R5, R6, R7, R8 , R9, R10, R11, R12, R13, and R14 each independently represent a hydrogen atom or an Ci-e alkyl group; X represents an oxygen atom, a sulfur atom, the formula: -CH2-, the formula: -C0- ,. or the formula: -NR2-, wherein R2 represents a hydrogen atom or a Ci_6 alkyl group; Y represents a single bond, the formula: -NR3CO-W-, the formula: - R3C0-W-0-, the formula: NR3C02-W-, the formula: -NR3- -, the formula: -NR3S0 = -W -, the formula: -NR3CONR4-W-, the formula: -NR3CO-W-NR4S02-, the formula: -S02NR3-W-, the formula: -CH2-W-, the formula: -CONR3-W-, the formula: -C0NR3-W-0-, the formula: -CH2-0-W-, the formula: -CH2 R3-W-, the formula: -CONR3-W- RCO-, the formula: -OW-, or the formula: -OWO-, wherein R3 and R4 each independently represents a hydrogen atom or a Ci_6 alkyl group, W is a single bond, a Ci-6 alkylene group, a C2-6 alkylene group including a carbon atom, carbon which is also a member of a C3-6 cycloalkyl ring, a C2_6 alkenylene group, or a C3_6 cycloalkylene group (provided that, when Y is the formula: -CO R3-W- R4CO- or the formula: - 0-WO-, W is not a single link); Z represents a benzene ring, a ring of pyrimidine, or a pyrazine ring; Ra represents a carboxy group, a carbamoyl group, a tetrazolyl group, or the formula: -CO HOH; Rb and R ° each independently represent a hydrogen atom, a halogen atom, or a Ci-6 alkyl group; Y Rd, Re, R £ and Rg each independently represents a hydrogen atom, a halogen atom, a Ci_6 alkyl group, or a Ci-e alkoxy group (provided that the compound is not acidic. 3- (butan-2-yloxy) benzyl] -6,7-dimethoxyiso-quinolin-4-yl.} Acetic acid (l- { [3- (butan-2-yl) phenyl] car-bonyl .) .6,6-dimethoxyisoquinolin-4-yl) acetic acid (l- { [3- (butan-2-yloxy) phenyl] carbonyl] -6,7-dimethoxyisoquinolin-4-yl) acetic acid, 2- (6,7-dimethoxy-l- { [3- (propaned-2-yloxy) phenyl] Carbo-nil.}. isoquinolin-4-yl) acetamide, (6,7-dimethoxy- l- { [3- (Propan-2-yloxy) phenyl] carbonyl}. isoquinolin-4-yl) acetic acid, 2- {6,7-dimethoxy-l- [(3-methoxyphenyl) carbonyl] isoquinolin-4-yl.} ace-tamide, or {6,6-dimethoxy-l- [(3-methoxyphenyl) -carbonyl] -isoquinolin-4-yl} -acetic acid); or a pharmaceutically acceptable salt thereof.
2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that Rd, R6, Rf and Rg each independently represent a hydrogen atom, a halogen atom, a Ci_6 alkyl group, or a Ci_6 alkoxy group ( except the compound or a salt pharmaceutically acceptable thereof in which both Rd and R9 are hydrogen atoms and both of Re and Rf are Ci_6 alkoxy group).
3. The compound or a pharmaceutically acceptable salt thereof agreed with claim 1 or 2, characterized in that: R1 is a Ci-6 alkyl group, a C2-6 alkenyl group, a C3_6 cycloalkyl group, a C3-6 cycloalkenyl group, an adamantyl group, an indanyl group, a tetrahydronaphthyl group, a tetrahydroindolyl group, a tetrahydropyranyl group, a group morpholinyl, a phenyl group, a naphthyl group, or an aromatic heterocyclic group, wherein the phenyl group, the naphthyl group, and the aromatic heterocyclic group may be substituted with 1 to 5 substituents selected from the group consisting of a Ci_6 alkyl group, a C2-6 alkenyl group, a C3_6 cycloalkyl group, a halogen atom, a Ci_6 alkoxy group, a hydroxy group, a C1-6 haloalkyl group, a C1-6 haloalkoxy group, a cyano group, a nitro group, a group C 1-6 alkylsulfonyl, a carboxy group, a phenyl group, a benzoyl group, a phenoxy group, the formula: -NR 5 R 6, and the formula: -S02 R 7 R 8; X is an oxygen atom, the formula: -CH2-, or the formula: -C0-; Z is a benzene ring; Ra is a carboxy group, a carbamoyl group, a group tetrazolyl, or the formula: -CONHOH; Rb and Rc each independently represents a hydrogen atom, or a Ci-6 alkyl group; Y Rd, Re, Rf and R9 each independently represents a hydrogen atom, a halogen atom, or a Ci_6 alkoxy group.
. The compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R1 is a Ci-6 alkyl group, a C3-6 cycloalkyl group, a phenyl group, a naphthyl group, or an aromatic heterocyclic group, wherein the phenyl group, the naphthyl group, and the aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from the group consisting of a Ci-6 alkyl group, a halogen atom, a C 1-6 alkoxy group, a hydroxy group, a C 1-6 alkylthio group, a C 1-6 haloalkyl group, a C 1-6 group 6 haloalkoxy, a C 1-6 haloalkylthio group, a cyano group, a nitro group, a guanidino group, a C 1-6 alkylsulfonyl group, a carboxy group, a C 2-7 alkoxycarbonyl group, a C 2-7 alkanoyloxy group, a phenyl group , a phenoxy group, a pyrrolyl group, a thienyl group, an imidazolyl group, a thiadiazolyl group, a morpholino group, the formula: -NR5R6, the formula: -S02NR7R8, the formula: -NR9S02R10, the formula: -C0NRnR12, and the formula: NR13COR1; And it is a single bond, the formula: -NR3CO-W-, the formula: -NR3CO-W-0-, the formula: NR3C02-W-, the formula: - R3-W-, the formula: -NR3S02-W -, the formula: R3CONR4-W-, the formula: -CONR3-W-, the formula: -0-W-, the formula: -CH20-, or the formula: -CH2NR3-; w is a single bond, a C1-6 alkylene group, a C2-6 alkenylene group, or a C3-6 cycloalkylene group; Ra is a carboxy group; Rb and Rc are each a hydrogen atom, and Rd, Re, Rf and R9 are each a hydrogen atom.
5. The compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R1 is a C1-6 alkyl group, a C3-6 cycloalkyl group, a phenyl group, a naphthyl group, or an aromatic heterocyclic group, wherein the phenyl group, the naphthyl group, and the aromatic heterocyclic group may be substituted with to 3 substituents selected from the group consisting of a Ci-e alkyl group, a halogen atom, a C 1-6 alkoxy group, a Ci_6 haloalkyl group, a Ci_6 haloalkoxy group, a cyano group, a nitro group, a phenyl group, a phenoxy group, and the formula: -NR5R6; X is the formula: -CH2-, or the formula: -CO-, - Y is the formula: -NR3C0-W-, the formula: -NR3C0-W-0-, the formula: - R3C02-W-, the Formula: -NR3-W-, the formula: - NR3S02-W-, the formula: - R3CONR -W-, or the formula: -0- -; W is a single bond, a Ci-6 alkylene group, a C2-6 alkenylene group, or a C3-6 cycloalkylene group; Z is a benzene ring; Ra is a carboxy group; Rb and Rc are each a hydrogen atom, and Rd, Re, Rf and Rg are each a hydrogen atom.
6. The compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that it is represented by the formula (II): [Ka 2] where, R1 'is a C3-6 cycloalkyl group, a C3_6 cycloalkenyl group, an adamantyl group, an indanyl group, a tetrahydronaphthyl group, a tetrahydroindolyl group, a phenyl group, a naphthyl group, or an aromatic heterocyclic group, wherein the phenyl group , the naphthyl group, and the aromatic heterocyclic group can be substituted with 1 to 5 substituents selected from the group consisting of a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 3-6 cycloalkyl group, a halogen atom, a Ci_6 alkoxy group, a hydroxy group, a Ci-6 haloalkyl group, a Ci_6 haloalkoxy group, a cyano group, a nitro group, a Ci-6 alkylsulfonyl group, a phenyl group, a benzoyl group, a phenoxy group, the formula: -NR5R6, and the formula: -S02 R7R8, wherein R5, R6, R7, and R8 each independently represent a hydrogen atom or a Ci-6 alkyl group; X 'is the formula: -CH2-, or the formula: -C0-; and W is a single bond, a Ci_6 alkylene group, a C2_6 alkenylene group, or a C3_6 cycloalkylene group.
7. The compound or a pharmaceutically acceptable salt thereof according to claim 6, characterized in that: R1 'is a C3-6 cycloalkyl group, a tetrahydronaphthyl group, a tetrahydroindolyl group, a phenyl group, a naphthyl group, an indolyl group, a benzofuranyl group, a benzothienyl group, a quinolyl group, or an iso-quinolyl group, wherein the phenyl group, the naphthyl group, the indolyl group, the benzofuranyl group, the benzothienyl group, the quinolyl group, and the isoquinolyl group may be substituted with 1 to 3 substituents selected from the group consisting of a Ci_6 alkyl group, an halogen, a C1-6 alkoxy group, a Ci_6 haloalkyl group, a C1-6 haloalkoxy group, a cyano group, a nitro group, a phenyl group, a phenoxy group, and the formula: -NR5R6.
8. The compound or a pharmaceutically acceptable salt thereof according to claim 6, characterized by: R1 'is a phenyl group, which may be substituted with 1 to 3 substituents selected from the group consisting of a Ci-6 alkyl group, a halogen atom, a Ci_6 alkoxy group, a Ci-6 haloalkyl group, a Ci_6 haloalkoxy group , a cyano group, a nitro group, a phenyl group, a phenoxy group, and the formula: - R5R6; Y W is a single link.
9. The compound or a pharmaceutically acceptable salt thereof according to any of claims 6 to 8, characterized in that X 'is the formula: -CH2-.
10. The compound or a pharmaceutically acceptable salt thereof according to claim 8, characterized in that X 'is the formula: -CO-.
11. The compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that it is represented by the formula (III): [Ka 3] where, R1"is a C3-6 cycloalkyl group, a group cycloalkenyl, an adamantyl group, a tetrahydronaphthyl group, a tetrahydroindolyl group, a phenyl group, a naphthyl group, or an aromatic heterocyclic group, wherein the phenyl group, the naphthyl group, and the aromatic heterocyclic group may be substituted by 1 to 5. substituents selected from the group consisting of a Ci-6 alkyl group, a C 3-6 cycloalkyl group, a halogen atom, a C 1-6 alkoxy group, a hydroxy group, a C 1-6 haloalkyl group, a C 1-6 haloalkoxy group , a cyano group, a nitro group, a phenyl group, a phenoxy group, and the formula: -NR5R6; R5 and R6 each independently represents a hydrogen atom or a C1-6 alkyl group; X "is the formula: -CH2-, or the formula: -CO-; W "is a single bond, a C2-6 alkylene group that includes a carbon atom that is also a member of a C3-6 cycloalkyl ring, or a Ci-6 alkylene group.
12. The compound or a pharmaceutically acceptable salt thereof according to claim 11, characterized in that: R1"is a C3.6 cycloalkyl group, an adamantyl group, a tetrahydronaphthyl group, a phenyl group, a naphthyl group, an indolyl group, a benzothiazolyl group, a benzofuranyl group, or a benzothienyl group, wherein the phenyl group, the naphthyl group, the indolyl group, the benzothiazolyl group, the benzofuranyl group, and the benzothienyl group may be substituted with 1 to 3 substituents selected from the group consisting of a Ci_6 alkyl group, a C3_6 cycloalkyl group, a halogen atom, a Ci_6 alkoxy group, a Ci-6 haloalkyl group, a Ci_6 haloalkoxy group, a phenyl group, and a pheno group i.
13. The compound or a pharmaceutically acceptable salt thereof according to claim 11 or 12, characterized in that X "is the formula: -CH2-.
14. The compound or a pharmaceutically acceptable salt thereof according to any of claims 11 to 13, characterized in that W "is a Ci-6 alkylene group.
MX2011006515A 2008-12-25 2009-12-25 Isoquinoline derivative. MX2011006515A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2008329064 2008-12-25
PCT/JP2009/071633 WO2010074244A1 (en) 2008-12-25 2009-12-25 Isoquinoline derivative

Publications (1)

Publication Number Publication Date
MX2011006515A true MX2011006515A (en) 2011-07-12

Family

ID=42287848

Family Applications (1)

Application Number Title Priority Date Filing Date
MX2011006515A MX2011006515A (en) 2008-12-25 2009-12-25 Isoquinoline derivative.

Country Status (15)

Country Link
US (1) US8461329B2 (en)
EP (1) EP2377851A4 (en)
JP (1) JPWO2010074244A1 (en)
KR (1) KR20110098749A (en)
CN (1) CN102264704B (en)
AU (1) AU2009331144A1 (en)
BR (1) BRPI0923592A2 (en)
CA (1) CA2747795A1 (en)
IL (1) IL213631A0 (en)
MX (1) MX2011006515A (en)
MY (1) MY150774A (en)
RU (1) RU2011130793A (en)
SG (1) SG172383A1 (en)
WO (1) WO2010074244A1 (en)
ZA (1) ZA201104421B (en)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011162274A1 (en) * 2010-06-23 2011-12-29 大正製薬株式会社 Isoquinoline derivative
KR20130133219A (en) * 2010-12-23 2013-12-06 머크 샤프 앤드 돔 코포레이션 Quinoxalines and aza-quinoxalines as crth2 receptor modulators
US9309212B2 (en) 2011-05-24 2016-04-12 The Wistar Institute Compositions and methods for modulating the activity of Epstein-Barr nuclear antigen 1
PL2781508T3 (en) * 2011-11-17 2019-06-28 Kbp Biosciences Co., Ltd. Nitrogen-containing fused ring compounds for use as crth2 antagonists
WO2013093508A2 (en) * 2011-12-22 2013-06-27 Oslo University Hospital Hf Wnt pathway inhibitors
TWI695831B (en) 2014-09-13 2020-06-11 香港商南北兄弟藥業投資有限公司 Compounds as crth2 antagonist and uses thereof
KR20210141778A (en) 2016-06-07 2021-11-23 자코바이오 파마슈티칼스 컴퍼니 리미티드 Novel heterocyclic derivatives useful as shp2 inhibitors
KR20220113545A (en) 2017-03-23 2022-08-12 자코바이오 파마슈티칼스 컴퍼니 리미티드 Novel heterocyclic derivatives useful as shp2 inhibitors
CN113135855B (en) * 2020-01-17 2023-01-24 江苏恒瑞医药股份有限公司 Preparation method of papaverine compound

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT1471057E (en) 2003-04-25 2006-05-31 Actimis Pharmaceuticals Inc UTEIS PYRIMIDYLINYL ACID DERIVATIVES FOR THE TREATMENT OF CRTH2 MEDIATED DISEASES
US7067529B2 (en) 2003-05-19 2006-06-27 Hoffmann-La Roche Inc. Glutamine fructose-y-phosphate amidotransferase (GFAT) inhibitors
SE0302232D0 (en) 2003-08-18 2003-08-18 Astrazeneca Ab Novel Compounds
MXPA06013912A (en) 2004-05-29 2007-07-18 7Tm Pharma As Crth2 receptor ligands for medicinal uses.

Also Published As

Publication number Publication date
CA2747795A1 (en) 2010-07-01
US20110288293A1 (en) 2011-11-24
US8461329B2 (en) 2013-06-11
SG172383A1 (en) 2011-07-28
KR20110098749A (en) 2011-09-01
EP2377851A4 (en) 2012-06-20
BRPI0923592A2 (en) 2016-01-26
WO2010074244A1 (en) 2010-07-01
JPWO2010074244A1 (en) 2012-06-21
ZA201104421B (en) 2012-08-29
MY150774A (en) 2014-02-28
CN102264704A (en) 2011-11-30
RU2011130793A (en) 2013-01-27
EP2377851A1 (en) 2011-10-19
AU2009331144A1 (en) 2011-07-14
IL213631A0 (en) 2011-07-31
CN102264704B (en) 2014-06-04

Similar Documents

Publication Publication Date Title
MX2011006515A (en) Isoquinoline derivative.
AU724549B2 (en) Indazole derivatives and their use as inhibitors of phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF)
CN113490664A (en) TYK2 inhibitors and uses thereof
AU2022356286B2 (en) Azetidine and pyrrolidine parp1 inhibitors and uses thereof
ES2407140T3 (en) Tetrahydroisoquinolyl sulfonamide derivatives, their preparation and their use in therapeutics
JP2013532692A (en) AMPK activated heterocyclic compounds and methods of use thereof
JP2007508374A (en) Bicyclic [3.1.0] derivatives as glycine transport inhibitors
KR20050074571A (en) Phenyl or heteroaryl amino alkane derivatives as ip receptor antagonist
IL173416A (en) Aminoquinoline derivatives, process for their preparation, pharmaceutical compositions containing them and uses thereof in the preparation of pharmaceutical compositions
WO2022048631A1 (en) Compound having antitumor activity and use thereof
CN105073117A (en) Tricyclic heterocycles as anticancer agents
ES2291958T3 (en) INDAZOL-3-ONAS AND ANALOGS AND DERIVATIVES OF THE SAME MODULES THAT MODULATE THE FUNCTION OF THE VAINILLOIDE-1 RECEIVER (VR1).
US9029378B2 (en) Substituted bicyclic aromatic carboxamide and urea compounds as vanilloid receptor ligands
WO2007018941A2 (en) Pyrimidyl-thiophene derivatives
EP1119562B1 (en) 2,3-dihydro-1h-isoindole derivatives useful as modulators of dopamine d3 receptors (antipsychotic agents)
MX2012014667A (en) Isoquinoline derivative.
KR20140085470A (en) Amine substituted methanesulfonamide derivatives as vanilloid receptor ligands
EP3130589A1 (en) Heterocyclic aza compounds
JP2012025742A (en) Medicine containing isoquinoline derivative
CN115043836B (en) P2X3 receptor selective modulator of imidazopyridine derivative and pharmaceutical application thereof
WO2024059249A1 (en) M4 activators/modulators and uses thereof
TW202000201A (en) Process for preparing 1-arylsulfonyl-pyrrolidine-2-carboxamide Transient Receptor Potential channel antagonist compounds and crystalline forms thereof

Legal Events

Date Code Title Description
FG Grant or registration